WO1996027583A1 - Arylsulfonylamino hydroxamic acid derivatives - Google Patents
Arylsulfonylamino hydroxamic acid derivativesDownload PDFInfo
- Publication number
- WO1996027583A1 WO1996027583A1PCT/US1996/002679US9602679WWO9627583A1WO 1996027583 A1WO1996027583 A1WO 1996027583A1US 9602679 WUS9602679 WUS 9602679WWO 9627583 A1WO9627583 A1WO 9627583A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- aryl
- amino
- heteroaryl
- hydrogen
- Prior art date
Links
- 0*N1CCCCC1Chemical compound*N1CCCCC10.000description5
Classifications
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/02—Local antiseptics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
Definitions
- the present inventionrelates to
- arylsulfonylamino hydroxamic acid derivativeswhich are inhibitors of matrix metalloproteinases or the
- TNFtumor necrosis factor
- This inventionalso relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans, and to the pharmaceutical compositions useful therefor.
- Matrix-degrading metalloproteinasessuch as gelatinase, stromelysin and collagenase, are involved in tissue matrix degradation (e.g. collagen collapse) and have been implicated in many pathological conditions involving abnormal connective tissue and basement membrane matrix metabolism, such as arthritis (e.g. osteoarthritis and rheumatoid arthritis), tissue ulceration (e.g. corneal, epidermal and gastric ulceration), abnormal wound healing, periodontal disease, bone disease (e.g. Paget's disease and
- osteoporosistumor metastasis or invasion, as well as HIV-infection (J. Leuk. Biol., 52 (2):244-248, 1992).
- Tumor necrosis factoris recognized to be involved in many infectious and auto-immune diseases (W. Friers, FEBS Letters, 1991, 285, 199).
- TNFis the prime mediator of the inflammatory response seen in sepsis and septic shock (C.E. Spooner et al., Clinical
- the present inventionrelates to a compound of the formula
- n1 to 6;
- Xis hydroxy, (C 1 -C 6 )alkoxy or NR 1 R 2 wherein R 1 and R 2 are each independently selected from the group consisting of hydrogen, (C 1 -C 6 ) alkyl, piperidyl, (C 1 -C 6 ) alkylpiperidyl, (C 6 -C 10 ) arylpiperidyl, (C 5 - C 9 )heteroarylpiperidyl, (C 6 -C 10 )aryl (C 1 - C 6 )alkylpiperidyl, (C 5 -C 9 )heteroaryl (C 1 - C 6 )alkylpiperidyl, (C 1 -C 6 )acylpiperidyl, (C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryl, (C 6 -C 10 )aryl (C 1 -C 6 )alkyl, (C 5 - C 9 )heteroaryl
- R 6(C 1 -C 6 )alkyl, (C 1 - C 5 )alkyl (CHR 6 )(C 1 -C 6 )alkyl wherein R 6 is piperidyl, (C 1 -C 6 )alkylpiperidyl, (C 6 -C 10 )arylpiperidyl, (C 6 -C 10 )aryl (C 1 -C 6 )alkylpiperidyl, (C 5 -C 9 )heteroarylpiperidyl or (C 5 -C 9 )heteroaryl (C 1 -C 6 )alkylpiperidyl; and CH(R 7 )COR 8 wherein R 7 is
- R 9OCO(C 1 -C 6 )alkyl wherein R 9 and R 10 are each
- R 11 and R 12are each independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl and (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkyl;
- R 1 and R 2 , or R 9 and R 10 , or R 11 and R 12may be taken together to form an azetidinyl
- ris 1, 2 or 3;
- n1 or 2;
- pis 0 or 1
- Qis hydrogen, (C 1 -C 3 )alkyl or (C 1 -C 6 )acyl;
- R 3 and R 4are each independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, trifluoromethyl, trifluoromethyl (C 1 -C 6 )alkyl, (C 1 - C 6 )alkyl (difluoromethylene), (C 1 - C 3 )alkyl (difluoromethylene) (C 1 -C 3 )alkyl, (C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 5 - C 9 )heteroaryl(C 1 -C 6 )alkyl, (C 8 -C 10 )aryl(C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 6
- R 3 and R 4 , or R 20 and R 21may be taken together to form a (C 3 -C 6 )cycloalkyl, oxacyclohexyl, thiocyclohexyl, indanyl or tetralinyl ring or a group of the formula
- R 15is hydrogen, (C 1 -C 6 )acyl, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkyl or (C 1 -C 6 )alkylsulfonyl; and
- Aris (C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryl, (C 1 - C 6 )alkyl(C 6 -C 10 )aryl, (C 1 -C 6 )alkoxy(C 6 -C 10 )aryl, ((C 1 - C 6 )alkoxy) 2 (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy(C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryloxy(C 6 -C 10 )aryl, (C 1 -C 6 )alkyl(C 5 - C 9 )heteroaryl, (C 1 -C 6 )alkoxy(C 5 -C 9 )heteroaryl, ((C 1 -C 6 )alkoxy(C 5 -C 9 )heteroaryl, ((C 1 -C 6 )aryloxy(C 5
- R 7 and R 8are as defined above, the other of R 1 or R 2 is hydrogen, (C 1 -C 6 )alkyl or benzyl.
- alkylas used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
- alkoxyincludes O-alkyl groups wherein “alkyl” is defined above.
- arylincludes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, (C 1 -C 6 )alkoxy, (C 6 -C 10 )aryloxy, trifluoromethoxy, difluoromethoxy and (C 1 -C 6 )alkyl.
- heteroarylincludes an organic radical derived from an aromatic heterocyclic compound by removal of one hydrogen, such as pyridyl, furyl, pyroyl, thienyl, isothiazolyl, imidazolyl,
- acylas used herein, unless otherwise indicated, includes a radical of the general formula RCO wherein R is alkyl, alkoxy, aryl, arylalkyl or aryalkyloxy and the terms “alkyl” or “aryl” are as defined above.
- the compound of formula Imay have chiral centers and therefore exist in different enantiomeric forms.
- This inventionrelates to all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof.
- Preferred compounds of formula Iinclude those wherein n is 2.
- R 15is (C 1 -C 6 )acyl, (C 1 -C 6 )alkyl, (C 6 - C 10 )aryl(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C 1 -C 6 )alkyl or
- More preferred compounds of formula Iare those wherein n is 2, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, R 1 and R 2 are taken together to form piperazinyl, (C 1 -C 6 )alkylpiperazinyl, (C 6 -C 10 )aryl piperazinyl or (C 5 -C 9 )heteroaryl (C 1 -C 6 )alkylpiperazinyl, and either R 3 or R 4 is not
- More preferred compounds of formula Iare those wherein n is 2, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, R 1 is hydrogen or (C 1 -C 6 ) alkyl, R 2 is 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl, and either R 3 or R 4 is not hydrogen or both R 3 and R 4 are not hydrogen.
- More preferred compounds of formula Iare those wherein n is 1, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, R 1 is hydrogen, R 2 is 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl, and either R 3 or R 4 is not hydrogen or both R 3 and R 4 are not hydrogen.
- More preferred compounds of formula Iare those wherein n is 2, Ar is 4-methoxyphenyl, R 1 is hydrogen or (C 1 -C 6 )alkyl and R 2 is R 5 (C 2 -C 8 )alkyl wherein R 5 is morpholino, thiomorpholino, piperidino, pyrrolidino, (C 1 -C 6 )acylpiperazino, (C 1 - C 6 )alkylpiperazino, (C 6 -C 10 )arylpiperazino, (C 5 - C 9 )heteroarylpiperazino, (C 6 -C 10 )aryl (C 1 - C 6 )alkylpiperazino or (C 5 -C 9 )heteroaryl (C 1 - C 6 )alkylpiperazino and either R 3 or R 4 is not hydrogen or both R 3 and R 4 are not hydrogen.
- More preferred compounds of formula Iare those wherein n is 1, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, R 1 is hydrogen, R 2 is R 5 (C 2 -C 6 )alkyl wherein R 5 is morpholino, thiomorpholino, piperidino, pyrrolidino (C 1 -C 6 )acylpiperazino, (C 1 -C 6 )alkylpiperazino, (C 6 -C 10 )arylpiperazino, (C 5 -C 9 )heteroarylpiperazino, (C 6 -C 10 )aryl (C 1 -C 6 )alkylpiperazino or (C 5 -C 9 )heteroaryl (C 1 -C 6 )alkylpiperazino and either R 3 or R 4 is not hydrogen or both R 3 and R 4 are not hydrogen.
- the present inventionalso relates to a pharmaceutical composition for (a) the treatment of a condition selected from the group consisting of
- tumor necrosis factorTNF
- TNFtumor necrosis factor
- a mammalincluding a human, comprising an amount of a compound of claim 1 or a
- the present inventionalso relates to a method for the inhibition of (a) matrix
- TNFtumor necrosis factor
- the present inventionalso relates to a method for treating a condition selected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, effective in treating such a condition.
- a conditionselected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said ma
- arylsulfonic acid compoundsuch as an arylsulfonyl chloride
- a basesuch as
- reaction mixtureis stirred, at room temperature, for time period between about 10 minutes to about 24 hours, preferably about 60 minutes.
- R 17 protecting groupis (C 1 -C 6 )alkyl, benzyl, allyl or tert-butyl, in the presence of a base such as potassium carbonate or sodium hydride, preferably sodium hydride, and a polar solvent, such as dimethylformamide.
- the reaction mixtureis stirred, at room temperature, for a time period between about 60 minutes to about 48 hours, preferably about 18 hours.
- the R 17 protecting groupis chosen such that it may be selectively removed in the presence of and without loss of the R 16 protecting group, therefore, R 17 cannot be the same as R 16 .
- R 17 protecting groupis carried out under conditions appropriate for that particular R 17 protecting group in use which will not affect the R 16 protecting group.
- Such conditionsinclude; (a) saponification where R 17 is (C 1 -C 6 )alkyl and R 16 is tert-butyl, (b) hydrogenolysis where R 17 is benzyl and R 16 is tert-butyl or (C 1 -C 6 )alkyl, (c) treatment with a strong acid such as trifluoroacetic acid or
- hydrochloric acidwhere R 17 is tert-butyl and R is (C 1 -C 6 )alkyl, benzyl or allyl, or (d) treatment with tributyltinhydride and acetic acid in the presence of catalytic bis (triphenylphosphine) palladium (II) chloride where R 17 is allyl and R 16 is (C 1 -C 6 )alkyl, benzyl or tert-butyl.
- the activated functional derivativemay be isolated prior to reaction with the primary or secondary amine or ammonia.
- the carboxylic acidmay be treated with oxalyl chloride or thionyl chloride, neat or in an inert solvent, such as chloroform, at a temperature between about 25°C. to about 80°C,
- condensation of the carboxylic acid of formula IV with an amine to provide the corresponding amide compound of formula IIIis the treatment of IV with (benzotriazol-1-yloxy) tris(dimethylamino) phosphonium .
- hexafluorophosphatein the presence of a base, such as triethylamine, to provide the benzotriazol-1-oxy ester in situ which, in turn, reacts with the amine, R 1 R 2 N, in an inert solvent, such as methylene chloride, at room temperature to give the amide compound of formula III.
- a basesuch as triethylamine
- conditionsinclude; (a) saponification where R 16 is lower alkyl, (b) hydrogenolysis where R 16 is benzyl, (c) treatment with a strong acid, such as
- hydroxamic acid compound of formula Iby treating II with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenztriazole in a polar solvent, such as dimethylformamide, followed by the addition of
- hydroxylamineto the reaction mixture after a time period between about 15 minutes to about 1 hour, preferably about 30 minutes.
- the hydroxylamineis preferably generated in situ from a salt form, such as hydroxylamine hydrochloride, in the presence of a base, such as N-methylmorpholine.
- a protected derivative of hydroxylamine or its salt form, where the hydroxyl group is protected as a tert-butyl, benzyl or allyl ethermay be used in the presence of
- protecting groupis carried out by hydrogenolysis for a benzyl protecting group or treatment with a strong acid, such as trifluoroacetic acid, for a tert-butyl protecting group.
- the allyl protecting groupmay be removed by treatment with tributyltinhydride and acetic acid in the presence of catalytic
- N,O-bis(4-methoxybenzyl) hydroxylaminemay also be used as the protected hydroxylamine derivative
- dimethylformamideat room temperature, for a time period between about 2 hours to about 48 hours, preferably about 18 hours.
- n2
- the oxidative cleavage of terminal olefins to carboxylic acidscan be achieved by several methods known in the art.
- the preferred method for the oxidative cleavage of the compound of formula VIII, wherein R 18 is 3-butenyl, to obtain the carboxylic acid compound of formula IVis to react VIII with sodium periodate in the presence of a catalytic amount of ruthenium (III) chloride in a mixture of carbon tetrachloride, acetonitrile and water.
- arylsulfonic acid compoundsuch as an arylsulfonyl chloride, at room temperature, in the presence of a suitable base, such as triethylamine, and a polar solvent such as tetrahydrofuran, dioxane, water or acetonitrile, preferably a mixture of dioxane and water, to give the corresponding dicarboxylic acid compound of formula XI.
- a suitable basesuch as triethylamine
- a polar solventsuch as tetrahydrofuran, dioxane, water or acetonitrile, preferably a mixture of dioxane and water
- cyclic anhydrides by dehydration of dicarboxylic acidsmay be achieved by a variety of means.
- the preferred method for the dehydration of the dicarboxylic acid compound of formula XI to give a cyclic anhydride compound of formula XIIis to treat XI with an excess of acetic anhydride at a temperature between about 25°C. to about 80°C, preferably about 60°C. Excess acetic anhydride and acetic acid, a by-product of the reaction, are removed by evaporation under reduced pressure leaving the cyclic anhydride compound of formula XII.
- anhydride compound of formula XIIis reacted, at room temperature, with an amine, NR 1 R 2 , or a salt of the amine, such as the hydrochloride, in the presence of a base, such as triethylamine, to give the carboxylic acid of formula II, wherein n is 1 and R 3 and R 4 are both hydrogen.
- Suitable solvents for the reactionare those that will not react with the starting materials, which include chloroform, methylene chloride and dimethylformamide, preferably methylene chloride.
- R 19is (C 1 -C 6 )alkyl or tert-butyl, in an inert solvent, such as toluene, at a temperature between about 60°C. to about 100°C, preferably about 100°C, for a time period between about 1 hour to about 3 hours, preferably 2 hours.
- the reactionis stirred, at room temperature, for a time period between about 60 minutes to about 48 hours, preferably about 18 hours.
- R 16cannot be the same as R 19 .
- Removal of the R 16 protecting group from the compound of formula XIII to give the corresponding carboxylic acid of formula XIV, wherein n is 1 to 6, in reaction 3 of Scheme 4is carried out under conditions appropriate for that particular R 16 protecting group in use which will not affect the R 19 (C 1 -C 6 )alkyl or tert-butyl group.
- Such conditionsinclude; (a) saponification where R 16 is (C 1 -C 6 )alkyl and R 19 is tert-butyl, (b) hydrogenolysis where R 16 is benzyl and R 19 is tert-butyl or (C 1 -C 6 )alkyl, (c) treatment with a strong acid such as trifluoroacetic acid or hydrochloric acid where R 16 is tert-butyl and
- R 19is (C 1 -C 6 )alkyl, or (d) treatment with
- tributyltinhydrideand acetic acid in the presence of catalytic bis (triphenylphosphine) palladium (II) chloride where R 16 is allyl and R 19 is (C 1 -C 6 )alkyl or tert-butyl.
- hydroxylamineis preferably generated in situ from a salt form, such as hydroxylamine hydrochloride, in the presence of a base, such as N-methylmorpholine.
- a protected derivative of hydroxylamine or its salt formwhere the hydroxyl group is protected as a tert-butyl, benzyl or allyl ether, may be used in the presence of
- protecting groupsis carried out by hydrogenolysis for a benzyl protecting group or treatment with a strong acid, such as trifluoroacetic acid, for a tert-butyl protecting group.
- the allyl protecting groupmay be removed by treatment with tributyltinhydride and acetic acid in the presence of catalytic
- N,O-bis(4-methoxybenzyl) hydroxylaminemay also be used, when R 19 is (C 1 -C 6 )alkyl, as the protected
- salts of the acidic compounds of the inventionare salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium,
- acid addition saltssuch as of mineral acids, organic carboxylic and organic sulfonic acids e.g. hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as pyridyl, constituted part of the structure.
- tumor necrosis factormetalloproteinase or the production of tumor necrosis factor is shown by the following in vitro assay tests.
- Human recombinant collagenaseis activated with trypsin using the following ratio: 10 ⁇ g trypsin per 100 ⁇ g of collagenase.
- the trypsin and collagenaseare incubated at room temperature for 10 minutes then a five fold excess (50 ⁇ g/10 ⁇ g trypsin) of soybean trypsin inhibitor is added.
- Collagenaseis diluted to 400 ng/ml and 25 ⁇ l is then added to appropriate wells of the microfluor plate. Final concentration of collagenase in the assay is 100 ng/ml .
- Substrate(DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH 2 ) is made as a 5 mM stock in dimethyl sulfoxide and then diluted to 20 ⁇ M in assay buffer. The assay is initiated by the addition of 50 ⁇ l
- Fluorescence readings(360 nM excitation, 460 nm emission) were taken at time 0 and then at 20 minute intervale. The assay is conducted at room temperature with a typical assay time of 3 hours.
- Fluorescence vs timeis then plotted for both the blank and collagenase containing samples (data from triplicate determinations is averaged). A time point that provides a good signal (the blank) and that is on a linear part of the curve (usually around 120 minutes) is chosen to determine IC 50 values. The zero time is used as a blank for each compound at each concentration and these values are subtracted from the 120 minute data. Data is plotted as inhibitor concentration vs % control (inhibitor fluorescence divided by fluorescence of collagenase alone x 100). IC 50 's are determined from the concentration of inhibitor that gives a signal that is 50% of the control.
- IC 50 'sare reported to be ⁇ 0.03 ⁇ M then the inhibitors are assayed at concentrations of 0.3 ⁇ M, 0.03 ⁇ M, 0.03 ⁇ M and 0.003 ⁇ M.
- MMP-2Inhibition of Gelatinase activity is assayed using the Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH 2 substrate (10 ⁇ M) under the same conditions as
- MMP-1human collagenase
- 72kD gelatinaseis activated with 1 mM APMA (p-aminophenyl mercuric acetate) for 15 hours at 4°C. and is diluted to give a final concentration in the assay of 100 mg/ml.
- Inhibitorsare diluted as for inhibition of human collagenase (MMP-1) to give final concentrations in the assay of 30 ⁇ M, 3 ⁇ M, 0.3 ⁇ M and 0.03 ⁇ M. Each concentration is done in triplicate.
- Fluorescence readings(360 nm excitation, 460 emission) are taken at time zero and then at 20 minutes intervale for 4 hours.
- IC 50 'sare determined as per inhibition of human collagenase (MMP-1). If IC 50 's are reported to be less than 0.03 ⁇ M, then the inhibitors are assayed at final concentrations of 0.3 ⁇ M, 0.03 ⁇ M, 0.003 ⁇ M and 0.003 ⁇ M.
- Human recombinant prostromelysinis activated with trypsin using a ratio of 1 ⁇ l of a 10 mg/ml trypsin stock per 26 ⁇ g of stromelysin.
- the trypsin and stromelysinare incubated at 37°C. for 15 minutes followed by 10 ⁇ l of 10 mg/ml soybean trypsin inhibitor for 10 minutes at 37°C. to quench trypsin activity.
- Assaysare conducted in a total volume of 250 ⁇ l of assay buffer (200 mM sodium chloride, 50 mM MES, and 10 mM calcium chloride, pH 6.0) in 96-well
- Activated stromelysinis diluted in assay buffer to 25 ⁇ g/ml.
- Ellman's reagent(3-Carboxy- 4-nitrophenyl disulfide) is made as a 1M stock in dimethyl formamide and diluted to 5 mM in assay buffer with 50 ⁇ l per well yielding at 1 mM final
- a 300 mM dimethyl sulfoxide stock solution of the peptide substrateis diluted to 15 mM in assay buffer and the assay is initiated by addition of 50 ⁇ l to each well to give a final concentration of 3 mM substrate.
- Blanksconsist of the peptide substrate and Ellman's reagent without the enzyme. Product formation was monitored at 405 nm with a Molecular Devices UVmax plate reader.
- IC 50 valueswere determined in the same manner as for collagenase.
- Human recombinant MMP-13is activated with 2mM APMA (p-aminophenyl mercuric acetate) for 1.5 hours, at 37°C. and is diluted to 400 mg/ml in assay buffer (50 mM Tris, pH 7.5, 200 mM sodium chloride, 5mM calcium chloride, 20 ⁇ M zinc chloride, 0.02% brij).
- assay buffer50 mM Tris, pH 7.5, 200 mM sodium chloride, 5mM calcium chloride, 20 ⁇ M zinc chloride, 0.02% brij.
- MMP-1human collagenase
- concentrations in the assayare 30 ⁇ M, 3 ⁇ M, 0.3 ⁇ M and
- Substrate(Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala- Lye(NMA)-NH 2 ) is prepared as for inhibition of human collagenase (MMP-1) and 50 ⁇ l is added to each well to give a final assay concentration of 10 ⁇ M. Fluorescence readings (360 nM excitation; 450 emission) are taken at time 0 and every 5 minutes for 1 hour.
- Positive controlsconsist of enzyme and substrate with no inhibitor and blanks consist of substrate only.
- IC 50 'sare determined as per inhibition of human collagenase (MMP-1). If IC 50 's are reported to be lees than 0.03 ⁇ M, inhibitors are then assayed at final concentrations of 0.3 ⁇ M, 0.03 ⁇ M, 0.003 ⁇ M and 0.0003 ⁇ M.
- Human mononuclear cellswere isolated from anti-coagulated human blood using a one-step Ficoll-hypaque separation technique. The mononuclear cells were washed three times in Hanks balanced salt solution (HBSS) with divalent cations and resuspended to a density of 2 ⁇ 10 6 /ml in HBSS containing 1% BSA.
- HBSSHanks balanced salt solution
- the active compoundwill be administered orally or parenterally at dosages between about 0.1 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg.
- dosagesbetween about 0.1 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg.
- some variation in dosagewill necessarily occur depending on the
- condition of the subjectbeing treated.
- the person responsible for administrationwill, in any event, determine the appropriate dose for the individual subject.
- the compounds of the present inventioncan be administered in a wide variety of different dosage forms, in general, the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
- tablets containing various excipientssuch as macrocrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various excipients.
- excipientssuch as macrocrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various excipients.
- disintegrantssuch as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelation and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
- Solid compositions of a similar typemay also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
- the active ingredientmay be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
- a sterile injectable solution of the active ingredientis usually prepared.
- Solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycolmay be employed.
- the aqueous solutionsshould be suitably adjusted and buffered, preferably at a pH of greater than 8, if necessary and the liquid diluent first rendered
- the oily solutionsare suitable for intraarticular, intramuscular and
- N-(4-Methoxybenzenesulfonyl)-D-valine benzyl ester(1.50 grams, 4.0 mmol) was added to a suspension of sodium hydride (0.1 grams, 4.2 mmol) in dry
- N-(4-Methoxybenzenesulfonyl)-D-valine benzyl ester(18.8 grams, 49.8 mmol) was added to a suspension of sodium hydride (1.3 grams, 54 mmol) in dry
- Example 3-6The title compounds of Examples 3-6 were prepared by a method analogous to that described in Example 2 using 2-(R)-2-[2-carboxyethyl(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester as the starting material which is coupled with the amine indicated.
- the catalystwas removed by filtration through nylon (pore size 0.45 ⁇ m) and the solvent was evaporated leaving 2-(R)-2- [(benzylmethylcarbamoylmethyl)(4- methoxybenzenesulfonyl)amino]-3-methylbutyric acid as a white foam, 902 mg (95%).
- Example 10-11The title compounds of Examples 10-11 were prepared by a method analogous to that described in Example 9 using 2-(R)-2-[carboxymethyl(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (Example 1) as the starting material which is coupled with the amine indicated.
- N-benzyloxy-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]acetamide(0.33 grams, 0.69 mmol) in methanol (35 mL) was added 5% palladium on activated carbon (85 mg). The mixture was agitated under 2 atmospheres hydrogen in a Parr shaker for 1.5 hours. The catalyst was removed by filtration through nylon (pore size 0.45 ⁇ m) and the solvent was evaporated.
- Example 15-16The title compounds of Examples 15-16 were prepared by a method analogous to that described in Example 14 using [carboxymethyl(4- methoxybenzenesulfonyl)amino]acetic acid as the
- thermospray: m/z 431 (M+H), 375, 314.
- thermospraym/z 375 (M+H), 314.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Virology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Dermatology (AREA)
- Cardiology (AREA)
- Pain & Pain Management (AREA)
- Tropical Medicine & Parasitology (AREA)
- Heart & Thoracic Surgery (AREA)
- Molecular Biology (AREA)
- AIDS & HIV (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Abstract
Description
ARYLSULFONYLAMINO HYDROXAMIC ACID DERIVATIVES
Background of the Invention
The present invention relates to
arylsulfonylamino hydroxamic acid derivatives which are inhibitors of matrix metalloproteinases or the
production of tumor necrosis factor (hereinafter also referred to as TNF) and as such are useful in the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of TNF.
This invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans, and to the pharmaceutical compositions useful therefor.
There are a number of enzymes which effect the breakdown of structural proteins and which are structurally related metalloproteases. Matrix-degrading metalloproteinases, such as gelatinase, stromelysin and collagenase, are involved in tissue matrix degradation (e.g. collagen collapse) and have been implicated in many pathological conditions involving abnormal connective tissue and basement membrane matrix metabolism, such as arthritis (e.g. osteoarthritis and rheumatoid arthritis), tissue ulceration (e.g. corneal, epidermal and gastric ulceration), abnormal wound healing, periodontal disease, bone disease (e.g. Paget's disease and
osteoporosis), tumor metastasis or invasion, as well as HIV-infection (J. Leuk. Biol., 52 (2):244-248, 1992).
Tumor necrosis factor is recognized to be involved in many infectious and auto-immune diseases (W. Friers, FEBS Letters, 1991, 285, 199).
Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (C.E. Spooner et al., Clinical
Immunology and Immunopathology, 1992, 62 S11).
Summary of the Invention
The present invention relates to a compound of the formula
n is 1 to 6;
X is hydroxy, (C1-C6)alkoxy or NR1R2 wherein R1 and R2 are each independently selected from the group consisting of hydrogen, (C1-C6) alkyl, piperidyl, (C1-C6) alkylpiperidyl, (C6-C10) arylpiperidyl, (C5- C9)heteroarylpiperidyl, (C6-C10)aryl (C1- C6)alkylpiperidyl, (C5-C9)heteroaryl (C1- C6)alkylpiperidyl, (C1-C6)acylpiperidyl, (C6-C10)aryl, (C5-C9)heteroaryl, (C6-C10)aryl (C1-C6)alkyl, (C5- C9)heteroaryl(C1-C6)alkyl, (C6-C10)aryl (C6-C10)aryl, (C6-C10)aryl (C6-C10)aryl (C1-C6)alkyl, (C3- C6)cycloalkyl, (C3-C8)cycloalkyl (C1-C6)alkyl, R5(C2- C6)alkyl, (C1-C5)alkyl(CHR5)(C1-C6)alkyl wherein R5 is hydroxy, (C1-C6)acyloxy, (C1-C6)alkoxy, piperazino, (C1-C6)alkylamino, (C1-C6)alkylthio, (C6-C10)arylthio, (C1-C6) alkylsulfinyl, (C6-C10)arylsulfinyl, (C1-C6)alkylsulfoxyl, (C6-C10)arylsulfoxyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)acylpiperazino, (C1-C6)alkylpiperazino, (C6-C10)aryl (C1-C6)alkylpiperazino, (C5-C9)heteroaryl (C1-C6)alkylpiperazino, morpholino, thiomorpholino,
piperidino or pyrrolidino; R6 (C1-C6)alkyl, (C1- C5)alkyl (CHR6)(C1-C6)alkyl wherein R6 is piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C6-C10)aryl (C1-C6)alkylpiperidyl, (C5-C9)heteroarylpiperidyl or (C5-C9)heteroaryl (C1-C6)alkylpiperidyl; and CH(R7)COR8 wherein R7 is
hydrogen, (C1-C6)alkyl, (C6-C10)aryl (C1-C6)alkyl, (C5- C9)heteroaryl (C1-C6)alkyl, (C1-C6)alkylthio(C1-C6)alkyl, (C6-C10)arylthio (C1-C6)alkyl, (C1-C6)alkylsulfinyl (C1-C6)alkyl, (C6-C10)arylsulfinyl (C1-C6)alkyl, (C1-C6)alkylsulfonyl (C1-C6)alkyl, (C6- C10)arylsulfonyl (C1-C6)alkyl, hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, (C1-C6)alkylamino (C1-C6)alkyl, ((C1-C6)alkylamino)2(C1-C6)alkyl, R9R10NCO(C1-C6)alkyl or
R9OCO(C1-C6)alkyl wherein R9 and R10 are each
independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl and
(C5-C9)heteroaryl(C1-C6)alkyl; and R8 is R11O or
R11R12N wherein R11 and R12 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl and (C5-C9)heteroaryl(C1-C6)alkyl;
or R1 and R2, or R9 and R10, or R11 and R12 may be taken together to form an azetidinyl,
pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, (C1-C6)acylpiperazinyl, (C1-C6)alkylpiperazinyl, (C6-C10)arylpiperazinyl, (C5- C9)heteroarylpiperazinyl or a bridged diazabicycloalkyl ring selected from the group consisting of
wherein r is 1, 2 or 3;
m is 1 or 2;
p is 0 or 1; and
Q is hydrogen, (C1-C3)alkyl or (C1-C6)acyl; R3 and R4 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, trifluoromethyl, trifluoromethyl (C1-C6)alkyl, (C1- C6)alkyl (difluoromethylene), (C1- C3)alkyl (difluoromethylene) (C1-C3)alkyl, (C6-C10)aryl, (C5-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C5- C9)heteroaryl(C1-C6)alkyl, (C8-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl, (C3- C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl,
hydroxy (C1-C6)alkyl, (C1-C6)acyloxy(C1-C6)alkyl, (C1- C6)alkoxy(C1-C6)alkyl, piperazinyl (C1-C6)alkyl, (C1- C6)acylamino(C1-C6)alkyl, piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)aryl(C1-C6)alkoxy (C1-C6)alkyl, (C5-C9)heteroaryl(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkylthio(C1-C6)alkyl, (C8-C10)arylthio(C1-C6)alkyl, (C1-C6)alkylsulfinyl(C1-C6)alkyl, (C6- C10)arylsulfinyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl (C1-C6)alkyl, (C6-C10)arylsulfonyl (C1-C6)alkyl, amino (C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkylamino)2(C1-C6)alkyl, R13CO(C1-C6)alkyl wherein R13 is R20O or R20R21N wherein R20 and R21 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl or (C5-C9)heteroaryl(C1-C6)alkyl; or R14 (C1-C6)alkyl wherein R14 is (C1-C6)acylpiperazino, (C6-C10)arylpiperazino, (C5-C9)heteroarylpiperazino, (C1- C6)alkylpiperazino, (C6-C10)aryl(C1-C6)alkylpiperazino, (C5-C9)heteroaryl (C1-C6)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C5- C9)heteroarylpiperidyl, (C6-C10)aryl(C1- C6)alkylpiperidyl, (C5-C9)heteroaryl(C1- C6)alkylpiperidyl or (C1-C6)acylpiperidyl;
or R3 and R4, or R20 and R21 may be taken together to form a (C3-C6)cycloalkyl, oxacyclohexyl, thiocyclohexyl, indanyl or tetralinyl ring or a group of the formula
Ar is (C6-C10)aryl, (C5-C9)heteroaryl, (C1- C6)alkyl(C6-C10)aryl, (C1-C6)alkoxy(C6-C10)aryl, ((C1- C6)alkoxy)2(C6-C10)aryl, (C6-C10)aryloxy(C6-C10)aryl, (C5-C9)heteroaryloxy(C6-C10)aryl, (C1-C6)alkyl(C5- C9)heteroaryl, (C1-C6)alkoxy(C5-C9)heteroaryl, ((C1-C6)alkoxy)2(C5-C9)heteroaryl, (C6-C10)aryloxy(C5-C9)heteroaryl, (C5-C9)heteroaryloxy(C5-C9)heteroaryl;
with the proviso that when either R1 or R2 is
CH(R7)COR8 wherein R7 and R8 are as defined above, the other of R1 or R2 is hydrogen, (C1-C6)alkyl or benzyl.
The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term "alkoxy", as used herein, includes O-alkyl groups wherein "alkyl" is defined above.
The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, (C1-C6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy and (C1-C6)alkyl.
The term "heteroaryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of one hydrogen, such as pyridyl, furyl, pyroyl, thienyl, isothiazolyl, imidazolyl,
benzimidazolyl, terazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl,
benzthiazolyl or benzoxazolyl, optionally substituted by 1 to 2 substituents selected from the group
consisting of fluoro, chloro, trifluoromethyl, (C1- C6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy,
difluoromethoxy and (C1-C6)alkyl.
The term "acyl", as used herein, unless otherwise indicated, includes a radical of the general formula RCO wherein R is alkyl, alkoxy, aryl, arylalkyl or aryalkyloxy and the terms "alkyl" or "aryl" are as defined above.
The term "acyloxy", as used herein, includes
O-acyl groups wherein "acyl" is defined above.
The compound of formula I may have chiral centers and therefore exist in different enantiomeric forms. This invention relates to all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof.
Preferred compounds of formula I include those wherein n is 2.
Other preferred compounds of formula I include those wherein Ar is 4-methoxyphenyl or 4-phenoxyphenyl.
Other preferred compounds of formula I include those wherein either R3 or R4 is not hydrogen.
Other preferred compounds of formula I include those wherein n is 1 and either R1 or R2 is hydrogen.
Other preferred compounds of formula I include those wherein X is hydroxy, Ar is 4-methoxyphenyl or 4-phenoxyphenyl and either R3 or R4 is not hydrogen.
Other preferred compounds of formula I include those wherein X is alkoxy, Ar is 4-methoxyphenyl or 4-phenoxyphenyl and either R3 or R4 is not hydrogen.
Other preferred compounds of formula I include those wherein Ar is 4-methoxyphenyl or 4-phenoxyphenyl and R3 and R4 are taken together to form
(C3-C6)cycloalkanyl, oxacyclohexanyl, thiocyclohexanyl, indanyl or a group of the formula
wherein R15 is (C1-C6)acyl, (C1-C6)alkyl, (C6- C10)aryl(C1-C6)alkyl, (C5-C9)heteroaryl(C1-C6)alkyl or
(C1-C6)alkylsulfonyl.
More preferred compounds of formula I are those wherein n is 2, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, R1 and R2 are taken together to form piperazinyl, (C1-C6)alkylpiperazinyl, (C6-C10)aryl piperazinyl or (C5-C9)heteroaryl (C1-C6)alkylpiperazinyl, and either R3 or R4 is not
hydrogen or both R3 and R4 are not hydrogen.
More preferred compounds of formula I are those wherein n is 2, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, R1 is hydrogen or (C1-C6) alkyl, R2 is 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl, and either R3 or R4 is not hydrogen or both R3 and R4 are not hydrogen.
More preferred compounds of formula I are those wherein n is 1, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, R1 is hydrogen, R2 is 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl, and either R3 or R4 is not hydrogen or both R3 and R4 are not hydrogen.
More preferred compounds of formula I are those wherein n is 2, Ar is 4-methoxyphenyl, R1 is hydrogen or (C1-C6)alkyl and R2 is R5 (C2-C8)alkyl wherein R5 is morpholino, thiomorpholino, piperidino, pyrrolidino, (C1-C6)acylpiperazino, (C1- C6)alkylpiperazino, (C6-C10)arylpiperazino, (C5- C9)heteroarylpiperazino, (C6-C10)aryl (C1- C6)alkylpiperazino or (C5-C9)heteroaryl (C1- C6)alkylpiperazino and either R3 or R4 is not hydrogen or both R3 and R4 are not hydrogen.
More preferred compounds of formula I are those wherein n is 1, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, R1 is hydrogen, R2 is R5 (C2-C6)alkyl wherein R5 is morpholino, thiomorpholino, piperidino, pyrrolidino (C1-C6)acylpiperazino, (C1-C6)alkylpiperazino, (C6-C10)arylpiperazino, (C5-C9)heteroarylpiperazino, (C6-C10)aryl (C1-C6)alkylpiperazino or (C5-C9)heteroaryl (C1-C6)alkylpiperazino and either R3 or R4 is not hydrogen or both R3 and R4 are not hydrogen.
Specific preferred compounds of formula I include the following:
2-(R)-N-Hydroxy-2-[(4-methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino]-3-methylbutyramide;
2-(R)-2-[(2-Benzylcarbamoylethyl)(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyramide;
2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)(2-[(pyridin-3-ylmethyl)carbamoyl]ethyl)amino)-3-methylbutyramide;
2-(R)-N-Hydroxy-2-([4-methoxybenzenesulfonyl][2-(methylpyridin-3-ylmethylcarbamoyl)ethyl]amino)-3-methylbutyramide;
4-(3-[1-(R)-1-Hydroxycarbamoy1-2-methylpropyl)(4-methoxybenzenesulfonyl)amino]propionyl)piperazine-1-carboxylic acid, tert-butyl ester;
2-(R)-N-Hydroxy-2-[(4-methoxybenzenesulfonyl)(3-oxo-3-piperazin-1-ylpropyl)amino)-3-methylbutyramide hydrochloride;
2-(R)-2-[(Benzylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino]N-hydroxy-3-methylbutyramide;
2-(R)-N-Hydroxy-2-([4-methoxybenzenesulfonyl]-[(2-morpholin-4-ylethylcarbamoyl)methyl]amino)-3-methylbutyramide; and
2-(R)-N-Hydroxy-2-((4- methoxybenzenesulfonyl)([(pyridin-3-ylmethyl)carbamoyl]methyl)amino)-3-methylbutyramide.
Other specific compounds of formula I include the foilowing:
2-(R)-3,3,3-Trifluoro-N-hydroxy-2- [(methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino]propionamide;
2-(R)-N-Hydroxy-2-((4-phenoxybenzenesulfonyl)[2-(methylpyridin-4-ylmethylcarbamoyl)ether]amino)-3-methylbutyramide;
4-[4-Methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino]-1-methylpiperidene-4-carboxylic acid hydroxyamide;
2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)-[3-(4-methylpiperazin-1-yl)-3-oxopropyl]amino)-3-methylbutyramide;
2-(R)-2-[(2-Carboxyethyl)(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyramide;
[(2-Carboxyethyl)(3,4-dimethoxybenzenesulfonyl)amino]-N-hydroxy-acetamide;
2-(R)-2-[(2-Carbamoylethyl)(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyramide;
2-(R),3-(R)-3,N-Dihydroxy-2-[(4-methoxybenzenesulfonyl)(3-oxo-3-piperidin-1-ylpropyl)amino]-butyramide;
2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)[3-(methylpyridin-3- ylmethylcarbamoyDpropyl]amino)-3-methylbutyramide;
2-(R)-N-Hydroxy-2-((4- methoxybenzenesulfonyl)[2- (methylcarboxymethylcarbamoyl)ethyl]amino)-3- methylbutyramide;
2-(R)-N-Hydroxy-2-((4- methoxybenzenesulfonyl)-[(1-methylpiperidin-4- ylcarbamoyl)methyl]amino)-3-methylbutyramide; 2-(R)-2-Cyclohexyl-N-hydroxy-2-((4-methoxybenzenesulfonyl)-[3-(4-methylpiperazin-1-yl)-3-oxopropyl]amino)-acetamide;
2- (R)-N-Hydroxy-2- [(methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino]-4-(morpholin-4-yl)butyramide.
The present invention also relates to a pharmaceutical composition for (a) the treatment of a condition selected from the group consisting of
arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix
metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) or (b) the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising an amount of a compound of claim 1 or a
pharmaceutically acceptable salt thereof, effective in such treatments and a pharmaceutically acceptable carrier.
The present invention also relates to a method for the inhibition of (a) matrix
metalloproteinases or (b) the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method for treating a condition selected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, effective in treating such a condition.
Detailed Description of the Invention
The following reaction Schemes illustrate the preparation of the compounds of the present invention.
Unless otherwise indicated R1, R2, R3, R4, n and Ar in the reaction Schemes and the discussion that follow are defined as above.
arylsulfonic acid compound, such as an arylsulfonyl chloride, in the presence of a base, such as
triethylamine, and a polar solvent, such as
tetrahydrofuran, dioxane, water or acetonitrile, preferably a mixture of dioxane and water. The
reaction mixture is stirred, at room temperature, for time period between about 10 minutes to about 24 hours, preferably about 60 minutes.
In reaction 2 of Scheme 1, the arylsulfonyl amino compound of formula VI, wherein R16 is (C1-C6)alkyl, benzyl, allyl or tert-butyl, is converted to the corresponding compound of formula V, wherein n is 1, 3, 4, 5 or 6, by reacting VI with a reactive
derivative of an alcohol of the formula
such as the chloride, bromide or iodide derivative, preferably the bromide derivative, wherein the R17 protecting group is (C1-C6)alkyl, benzyl, allyl or tert-butyl, in the presence of a base such as potassium carbonate or sodium hydride, preferably sodium hydride, and a polar solvent, such as dimethylformamide. The reaction mixture is stirred, at room temperature, for a time period between about 60 minutes to about 48 hours, preferably about 18 hours. The R17 protecting group is chosen such that it may be selectively removed in the presence of and without loss of the R16 protecting group, therefore, R17 cannot be the same as R16.
Removal of the R17 protecting group from the compound of formula V to give the corresponding carboxylic acid of formula IV, in reaction 3 of Scheme 1, is carried out under conditions appropriate for that particular R17 protecting group in use which will not affect the R16 protecting group. Such conditions include; (a) saponification where R17 is (C1-C6)alkyl and R16 is tert-butyl, (b) hydrogenolysis where R17 is benzyl and R16 is tert-butyl or (C1-C6)alkyl, (c) treatment with a strong acid such as trifluoroacetic acid or
hydrochloric acid where R17 is tert-butyl and R is (C1-C6)alkyl, benzyl or allyl, or (d) treatment with tributyltinhydride and acetic acid in the presence of catalytic bis (triphenylphosphine) palladium (II) chloride where R17 is allyl and R16 is (C1-C6)alkyl, benzyl or tert-butyl.
In reaction 4 of Scheme 1, the carboxylic acid of formula IV is condensed with an amine, R1R2NH, or the salt thereof, to give the corresponding amide compound of formula III. The formation of amides from primary or secondary amines or ammonia and carboxylic acids is achieved by conversion of the carboxylic acid to an activated functional derivative which
subsequently undergoes reaction with a primary or secondary amine or ammonia to form the amide. The activated functional derivative may be isolated prior to reaction with the primary or secondary amine or ammonia. Alternatively, the carboxylic acid may be treated with oxalyl chloride or thionyl chloride, neat or in an inert solvent, such as chloroform, at a temperature between about 25°C. to about 80°C,
preferably about 50°C, to give the corresponding acid chloride functional derivative. The inert solvent and any remaining oxalyl chloride or thionyl chloride is then removed by evaporation under vacuum. The
remaining acid chloride functional derivative is then reacted with the primary or secondary amine or ammonia in an inert solvent, such as methylene chloride, to form the amide. The preferred method for the
condensation of the carboxylic acid of formula IV with an amine to provide the corresponding amide compound of formula III is the treatment of IV with (benzotriazol-1-yloxy) tris(dimethylamino) phosphonium .
hexafluorophosphate in the presence of a base, such as triethylamine, to provide the benzotriazol-1-oxy ester in situ which, in turn, reacts with the amine, R1R2N, in an inert solvent, such as methylene chloride, at room temperature to give the amide compound of formula III.
Removal of the R16 protecting group from the compound of formula III to give the corresponding carboxylic acid of formula II, in reaction 5 of Scheme 1 , is carried out under conditions appropriate for the particular R16 protecting group in use. Such
conditions include; (a) saponification where R16 is lower alkyl, (b) hydrogenolysis where R16 is benzyl, (c) treatment with a strong acid, such as
trifluoroacetic acid or hydrochloric acid, where R16 is tert-butyl, or (d) treatment with tributyltinhydride and acetic acid in the presence of catalytic
bis(triphenylphosphine) palladium (II) chloride where R16 is allyl.
In reaction 6 of Scheme 1 , the carboxylic acid compound of formula II is converted to the
hydroxamic acid compound of formula I by treating II with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenztriazole in a polar solvent, such as dimethylformamide, followed by the addition of
hydroxylamine to the reaction mixture after a time period between about 15 minutes to about 1 hour, preferably about 30 minutes. The hydroxylamine is preferably generated in situ from a salt form, such as hydroxylamine hydrochloride, in the presence of a base, such as N-methylmorpholine. Alternatively, a protected derivative of hydroxylamine or its salt form, where the hydroxyl group is protected as a tert-butyl, benzyl or allyl ether, may be used in the presence of
(benzotriazol-1-yloxy) tris(dimethylamino) phosphonium hexafluorophosphate and a base, such as Nmethylmorpholine. Removal of the hydroxylamine
protecting group is carried out by hydrogenolysis for a benzyl protecting group or treatment with a strong acid, such as trifluoroacetic acid, for a tert-butyl protecting group. The allyl protecting group may be removed by treatment with tributyltinhydride and acetic acid in the presence of catalytic
bis(triphenylphosphine) palladium (II) chloride. N,O-bis(4-methoxybenzyl) hydroxylamine may also be used as the protected hydroxylamine derivative where
deprotection is achieved using a mixture of
methanesulfonic acid and trifluoroacetic acid.
In reaction 1 of Scheme 2 , the
aryleulfonylami.no compound of formula VI, wherein R16 is (C1-C6)alkyl, benzyl or tert-butyl, is converted to the corresponding compound of formula VIII, wherein R18 is 2-propenyl or 3-butenyl, by reacting IX with a reactive functional derivative, such as the halide, preferably the iodide derivative, of 2-propen-1-ol when R18 is 2-propenyl or 3-buten-1-ol when R18 is 3-butenyl, in the presence of a base, such as potassium carbonate, cesium carbonate or sodium hydride,
preferably Bodium hydride when R18 is 2-propenyl or cesium carbonate when R18 is 3-butenyl. The reaction is stirred in a polar solvent, such as
dimethylformamide, at room temperature, for a time period between about 2 hours to about 48 hours, preferably about 18 hours.
In reaction 2 of Scheme 2 , the compound of formula VIII is converted to the carboxylic acid compound of formula IV, wherein n is 2. The compound of formula VIII, wherein R18 is 2-propenyl, is
converted to the compound of formula IV, wherein n is 2, by reacting VIII with borane-dimethylsulfide complex, followed by immediate oxidation using chromium trioxide in aqueous acetic acid. The oxidative cleavage of terminal olefins to carboxylic acids can be achieved by several methods known in the art. The preferred method for the oxidative cleavage of the compound of formula VIII, wherein R18 is 3-butenyl, to obtain the carboxylic acid compound of formula IV is to react VIII with sodium periodate in the presence of a catalytic amount of ruthenium (III) chloride in a mixture of carbon tetrachloride, acetonitrile and water.
The compound of formula IV, wherein n is 2, is further reacted to provide the hydroxamic acid compound of formula I, wherein n is 2, according to the procedure described above in reactions 4, 5 and 6 of Scheme 1.
An alternative method for the synthesis of the hydroxamic acid compound of formula I, wherein n is 1 and R3 and R4 are both hydrogen, is shown in reaction
1 of Scheme 3, beginning with reacting iminoacetic acid or a metal or ammonium salt of iminoacetic acid of formula X with a functional derivative of an
arylsulfonic acid compound, such as an arylsulfonyl chloride, at room temperature, in the presence of a suitable base, such as triethylamine, and a polar solvent such as tetrahydrofuran, dioxane, water or acetonitrile, preferably a mixture of dioxane and water, to give the corresponding dicarboxylic acid compound of formula XI.
In reaction 2 of Scheme 3., the dicarboxylic acid compound of formula XI is dehydrated to give a cyclic anhydride compound of formula XII. The
formation of cyclic anhydrides by dehydration of dicarboxylic acids may be achieved by a variety of means. The preferred method for the dehydration of the dicarboxylic acid compound of formula XI to give a cyclic anhydride compound of formula XII is to treat XI with an excess of acetic anhydride at a temperature between about 25°C. to about 80°C, preferably about 60°C. Excess acetic anhydride and acetic acid, a by-product of the reaction, are removed by evaporation under reduced pressure leaving the cyclic anhydride compound of formula XII.
In reaction 3 of Scheme 3, the cyclic
anhydride compound of formula XII is reacted, at room temperature, with an amine, NR1R2, or a salt of the amine, such as the hydrochloride, in the presence of a base, such as triethylamine, to give the carboxylic acid of formula II, wherein n is 1 and R3 and R4 are both hydrogen. Suitable solvents for the reaction are those that will not react with the starting materials, which include chloroform, methylene chloride and dimethylformamide, preferably methylene chloride.
The compound of formula II is further reacted to give the hydroxamic acid compound of formula I, wherein n is 1 and R3 and R4 are both hydrogen,
according to the procedure described above in reaction
6 of Scheme 1.
In reaction 1 of Scheme 4, the carboxylic acid compound of formula IV, wherein n is 2, is
converted to the corresponding compound of formula V, wherein R19 is (C1-C6)alkyl or tert-butyl, by reacting
IV with a compound of the formula
(R19O)2CHN(CH3)2
wherein R19 is (C1-C6)alkyl or tert-butyl, in an inert solvent, such as toluene, at a temperature between about 60°C. to about 100°C, preferably about 100°C, for a time period between about 1 hour to about 3 hours, preferably 2 hours. In reaction 2 of Scheme 4., the arylsulfonyl amino compound of formula VI wherein n is 1, 3, 4, 5 or 6 and R16 is (C1-C6)alkyl, benzyl, allyl or tert-butyl, is converted to the corresponding compound of formula XIII, wherein R19 is (C1-C6)alkyl or tert-butyl, by reacting VI with a reactive
derivative of an alcohol of the formula
such as the chloride, bromide or iodide derivative, preferably the bromide derivative, wherein R19 is (C1-C6)alkyl or tert-butyl, in the presence of a base such as potassium carbonate or sodium hydride, preferably sodium hydride, and a polar solvent, such as
dimethylformamide. The reaction is stirred, at room temperature, for a time period between about 60 minutes to about 48 hours, preferably about 18 hours. The R16 protecting group, of the compounds of formulae IV and
VI, is chosen such that it may be selectively removed in the presence of and without lose of the R19
(C1-C6)alkyl or tert-butyl group, therefore, R16 cannot be the same as R19. Removal of the R16 protecting group from the compound of formula XIII to give the corresponding carboxylic acid of formula XIV, wherein n is 1 to 6, in reaction 3 of Scheme 4 , is carried out under conditions appropriate for that particular R16 protecting group in use which will not affect the R19 (C1-C6)alkyl or tert-butyl group. Such conditions include; (a) saponification where R16 is (C1-C6)alkyl and R19 is tert-butyl, (b) hydrogenolysis where R16 is benzyl and R19 is tert-butyl or (C1-C6)alkyl, (c) treatment with a strong acid such as trifluoroacetic acid or hydrochloric acid where R16 is tert-butyl and
R19 is (C1-C6)alkyl, or (d) treatment with
tributyltinhydride and acetic acid in the presence of catalytic bis (triphenylphosphine) palladium (II) chloride where R16 is allyl and R19 is (C1-C6)alkyl or tert-butyl.
In reaction 4 of Scheme 4 , the carboxylic acid of formula XIV is converted to the hydroxamic acid compound of formula XV, wherein n is 1 to 6, by
treating XIV with 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide and 1-hydroxybenztriazole in a polar solvent, such as dimethylformamide, followed by the addition of hydroxylamine to the reaction mixture after a time period between about 15 minutes to about 1 hour, preferably about 30 minutes. The hydroxylamine is preferably generated in situ from a salt form, such as hydroxylamine hydrochloride, in the presence of a base, such as N-methylmorpholine. Alternatively, a protected derivative of hydroxylamine or its salt form, where the hydroxyl group is protected as a tert-butyl, benzyl or allyl ether, may be used in the presence of
(benzotriazol-1-yloxy) tris(dimethylamino) phosphonium hexafluorophosphate and a base, such as N-methylmorpholine. Removal of the hydroxylamine
protecting groups is carried out by hydrogenolysis for a benzyl protecting group or treatment with a strong acid, such as trifluoroacetic acid, for a tert-butyl protecting group. The allyl protecting group may be removed by treatment with tributyltinhydride and acetic acid in the presence of catalytic
bis(triphenylphosphine) palladium (II) chloride. N,O-bis(4-methoxybenzyl) hydroxylamine may also be used, when R19 is (C1-C6)alkyl, as the protected
hydroxylamine derivative where deprotection is achieved using a mixture of methanesulfonic acid and
trifluoroacetic acid.
In reaction 5 of Scheme 4, the amide formula of formula XV is, if desired, converted to the
corresponding carboxylic acid compound of formula XVI by (a) saponification where R9 is lower alkyl or (b) treatment with a strong acid, such as trifluoroacetic acid or hydrochloric acid, where R19 is tert-butyl.
Pharmaceutically acceptable salts of the acidic compounds of the invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium,
diethylammonium, and tris-(hydroxymethyl)- methylammonium salts.
Similarly acid addition salts, such as of mineral acids, organic carboxylic and organic sulfonic acids e.g. hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as pyridyl, constituted part of the structure.
The ability of the compounds of formula I or their pharmaceutically acceptable salts (hereinafter also referred to as the compounds of the present invention) to inhibit matrix metalloproteinases or the production of tumor necrosis factor (TNF) and,
consequently, demonstrate their effectiveness for treating diseases characterized by matrix
metalloproteinase or the production of tumor necrosis factor is shown by the following in vitro assay tests.
Biological Assay
Inhibition of Human Collagenase (MMP-1)
Human recombinant collagenase is activated with trypsin using the following ratio: 10 μg trypsin per 100 μg of collagenase. The trypsin and collagenase are incubated at room temperature for 10 minutes then a five fold excess (50 μg/10 μg trypsin) of soybean trypsin inhibitor is added.
10 mM stock solutions of inhibitors are made up in dimethyl sulfoxide and then diluted using the following Scheme:
10 mM > 120 μM > 12 μM > 1.2 μM > 0.12 μM
Twenty-five microliters of each concentration is then added in triplicate to appropriate wells of a 96 well microfluor plate. The final concentration of inhibitor will be a 1:4 dilution after addition of enzyme and substrate. Positive controls (enzyme, no inhibitor) are set up in wells D1-D6 and blanks (no enzyme, no inhibitors) are set in wells D7-D12.
Collagenase is diluted to 400 ng/ml and 25 μl is then added to appropriate wells of the microfluor plate. Final concentration of collagenase in the assay is 100 ng/ml .
Substrate (DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2) is made as a 5 mM stock in dimethyl sulfoxide and then diluted to 20 μM in assay buffer. The assay is initiated by the addition of 50 μl
substrate per well of the microfluor plate to give a final concentration of 10 μM.
Fluorescence readings (360 nM excitation, 460 nm emission) were taken at time 0 and then at 20 minute intervale. The assay is conducted at room temperature with a typical assay time of 3 hours.
Fluorescence vs time is then plotted for both the blank and collagenase containing samples (data from triplicate determinations is averaged). A time point that provides a good signal (the blank) and that is on a linear part of the curve (usually around 120 minutes) is chosen to determine IC50 values. The zero time is used as a blank for each compound at each concentration and these values are subtracted from the 120 minute data. Data is plotted as inhibitor concentration vs % control (inhibitor fluorescence divided by fluorescence of collagenase alone x 100). IC50's are determined from the concentration of inhibitor that gives a signal that is 50% of the control.
If IC50's are reported to be <0.03 μM then the inhibitors are assayed at concentrations of 0.3 μM, 0.03 μM, 0.03 μM and 0.003 μM.
Inhibition of Gelatinase (MMP-2) Inhibition of gelatinase activity is assayed using the Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2 substrate (10 μM) under the same conditions as
inhibition of human collagenase (MMP-1).
72kD gelatinase is activated with 1 mM APMA (p-aminophenyl mercuric acetate) for 15 hours at 4°C. and is diluted to give a final concentration in the assay of 100 mg/ml. Inhibitors are diluted as for inhibition of human collagenase (MMP-1) to give final concentrations in the assay of 30 μM, 3 μM, 0.3 μM and 0.03 μM. Each concentration is done in triplicate.
Fluorescence readings (360 nm excitation, 460 emission) are taken at time zero and then at 20 minutes intervale for 4 hours.
IC50's are determined as per inhibition of human collagenase (MMP-1). If IC50's are reported to be less than 0.03 μM, then the inhibitors are assayed at final concentrations of 0.3 μM, 0.03 μM, 0.003 μM and 0.003 μM.
Inhibition of Stromelysin Activity (MMP-3)
Inhibition of stromelysin activity is based on a modified spectrophotometric assay described by Weingarten and Feder (Weingarten, H. and Feder, J., Spectrophotometric Assay for Vertebrate Collagenase,
Anal. Biochem. 147, 437-440 (1985)). Hydrolysis of the thio peptolide substrate [Ac-Pro-Leu-Gly-SCH[CH2CH(CH3)2]CO-Leu-Gly-OC2H5] yields a mercaptan fragment that can be monitored in the presence of
Ellman's reagent.
Human recombinant prostromelysin is activated with trypsin using a ratio of 1 μl of a 10 mg/ml trypsin stock per 26 μg of stromelysin. The trypsin and stromelysin are incubated at 37°C. for 15 minutes followed by 10 μl of 10 mg/ml soybean trypsin inhibitor for 10 minutes at 37°C. to quench trypsin activity.
Assays are conducted in a total volume of 250 μl of assay buffer (200 mM sodium chloride, 50 mM MES, and 10 mM calcium chloride, pH 6.0) in 96-well
microliter plates. Activated stromelysin is diluted in assay buffer to 25 μg/ml. Ellman's reagent (3-Carboxy- 4-nitrophenyl disulfide) is made as a 1M stock in dimethyl formamide and diluted to 5 mM in assay buffer with 50 μl per well yielding at 1 mM final
concentration.
10 mM stock solutions of inhibitors are made in dimethyl sulfoxide and diluted serially in assay buffer such that addition of 50 μL to the appropriate wells yields final concentrations of 3 μM, 0.3 μM, 0.003 μM, and 0.0003 μM. All conditions are completed in triplicate.
A 300 mM dimethyl sulfoxide stock solution of the peptide substrate is diluted to 15 mM in assay buffer and the assay is initiated by addition of 50 μl to each well to give a final concentration of 3 mM substrate. Blanks consist of the peptide substrate and Ellman's reagent without the enzyme. Product formation was monitored at 405 nm with a Molecular Devices UVmax plate reader.
IC50 values were determined in the same manner as for collagenase.
Inhibition of MMP-13
Human recombinant MMP-13 is activated with 2mM APMA (p-aminophenyl mercuric acetate) for 1.5 hours, at 37°C. and is diluted to 400 mg/ml in assay buffer (50 mM Tris, pH 7.5, 200 mM sodium chloride, 5mM calcium chloride, 20μM zinc chloride, 0.02% brij).
Twenty-five microliters of diluted enzyme is added per well of a 96 well microfluor plate. The enzyme is then diluted in a 1:4 ratio in the assay by the addition of inhibitor and substrate to give a final concentration in the assay of 100 mg/ml.
10 mM stock solutions of inhibitors are made up in dimethyl sulfoxide and then diluted in assay buffer as per the inhibitor dilution scheme for
inhibition of human collagenase (MMP-1): Twenty-five microliters of each concentration is added in
triplicate to the microfluor plate. The final
concentrations in the assay are 30 μM, 3 μM, 0.3 μM and
0.03 μM.
Substrate (Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala- Lye(NMA)-NH2) is prepared as for inhibition of human collagenase (MMP-1) and 50 μl is added to each well to give a final assay concentration of 10 μM. Fluorescence readings (360 nM excitation; 450 emission) are taken at time 0 and every 5 minutes for 1 hour.
Positive controls consist of enzyme and substrate with no inhibitor and blanks consist of substrate only.
IC50's are determined as per inhibition of human collagenase (MMP-1). If IC50's are reported to be lees than 0.03 μM, inhibitors are then assayed at final concentrations of 0.3 μM, 0.03 μM, 0.003 μM and 0.0003 μM.
Inhibition of TNF Production
The ability of the compounds or the pharmaceutically acceptable salts thereof to inhibit the production of TNF and, consequently, demonstrate their effectiveness for treating diseases involving the production of TNF is shown by the following in vitro assay:
Human mononuclear cells were isolated from anti-coagulated human blood using a one-step Ficoll-hypaque separation technique. The mononuclear cells were washed three times in Hanks balanced salt solution (HBSS) with divalent cations and resuspended to a density of 2 × 106/ml in HBSS containing 1% BSA.
Differential counts determined using the Abbott Cell Dyn 3500 analyzer indicated that monocytes ranged from 17 to 24% of the total cells in these preparations.
180μ of the cell suspension was aliquoted into flate bottom 96 well plates (Costar). Additions of compounds and LPS (100ng/ml final concentration) gave a final volume of 200μl. All conditions were performed in triplicate. After a four hour incubation at 37°C. in an humidified CO2 incubator, plates were removed and centrifuged (10 minutes at approximately 250 x g) and the supernatants removed and assayed for TNFα using the R&D ELISA Kit.
For administration to humane for the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF), a variety of conventional routes may be used including orally, parenterally and topically. In general, the active compound will be administered orally or parenterally at dosages between about 0.1 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg. However, some variation in dosage will necessarily occur depending on the
condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
The compounds of the present invention can be administered in a wide variety of different dosage forms, in general, the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
For oral administration, tablets containing various excipients such as macrocrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various
disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelation and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration (intramuscular, intraperitoneal, subcutaneous and intravenous use) a sterile injectable solution of the active ingredient is usually prepared. Solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably adjusted and buffered, preferably at a pH of greater than 8, if necessary and the liquid diluent first rendered
isotonic. These aqueous solutions are suitable
intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and
subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
The present invention is illustrated by the following examples, but it is not limited to the details thereof.
EXAMPLE 1
2-(R)-N-Hydroxy-2-[(-methoxybenzenesulfonyl) (2-morpholin-4-yl-2-oxoethyl)amino]-3-methylbutyramide
To a solution of D-valine benzyl ester hydrochloride (2.4 grams, 10 mmol) and triethylamine (2.5 grams, 3.5 mL, 25 mmol) in water (50 mL) and 1,4- dioxane (50 mL) is added 4-methoxybenzenesulfonyl chloride (2.3 grams, 11 mmol). The mixture was stirred at room temperature for 1 hour and then most of the solvent was removed by evaporation under vacuum. The mixture was diluted with ethyl acetate and was washed successively with dilute hydrochloric acid solution, water and brine. The organic solution was dried over magnesium sulfate and concentrated to leave N-(4- methoxybenzenesulfonyl)-D-valine benzyl ester as a white solid, 3.6 grams (97%); m.p. 92-94°C.
N-(4-Methoxybenzenesulfonyl)-D-valine benzyl ester (1.50 grams, 4.0 mmol) was added to a suspension of sodium hydride (0.1 grams, 4.2 mmol) in dry
dimethylformamide (20 mL) and, after 30 minutes, tert-butyl bromoacetate (0.8 mL, 4.2 mmol) was added. The resulting mixture was stirred overnight at room
temperature and was then quenched by addition of saturated ammonium chloride solution (3 mL). The dimethylformamide was removed by evaporation under vacuum. The residue was taken up in ethyl acetate and washed with water and brine. After drying over
magnesium sulfate, ethyl acetate was evaporated to leave an oil from which 2-(R)-2-[tert-butoxycarbonylmethyl(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester, a clear oil (1.92 grams, 98%), was isolated using flash chromatography on silica gel eluting with 15% ethyl acetate in hexane.
To a cold (0°C.) solution of 2-(R)-2-[tert-butoxycarbonylmethyl(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (1.92 grams, 3.9 mmol) in methylene chloride (28 mL) was added trifluoroacetic acid (7 mL). The resulting solution was allowed to warm to room temperature and was stirred overnight.
The methylene chloride and trifluoroacetic acid were evaporated under vacuum leaving 2-(R)-2- [carboxymethyl(4-methoxybenzenesulfonyl)amino)]-3-methylbutyric acid benzyl ester as a clear oil, 1.70 grams (100%).
To a solution of 2-(R)-2-[carboxymethyl(4- methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (573 mg, 1.32 mmol) in methylene chloride (12 mL) were added sequentially triethylamine (0.46 mL, 3.28 mmol), morpholine (0.127 mL, 1.46 mmol) and
(benzotriazol-1-yloxy)tris(dimethylamino) phosphonium hexafluorophosphate (646 mg, 1.46 mmol). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed with 0.5 N hydrochloric acid solution and brine, dried over magnesium sulfate and concentrated under vacuum. The residue was chromatographed on silica gel using 40% ethyl acetate in hexane affording 2-(R)-2-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-oxoethyl)amino]-3-methylbutyric acid benzyl ester as a clear oil, 590 mg (89%).
To a solution of 2-(R)-2-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]-3-methylbutyric acid benzyl ester (590 mg, 1.17 mmol) in ethanol (50 mL) was added 10%
palladium on activated carbon (200 mg). The mixture was agitated under 3 atmospheres hydrogen in a Parr shaker for 2 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated leaving 2-(R)-2-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]-3-methylbutyric acid as a white foam, 485 mg (100%).
To a solution of 2-(R)-2-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]-3-methylbutyric acid (485 mg, 1.17 mmol) in methylene chloride (12 mL) were added
sequentially triethylamine (0.52 mL, 3.71 mmol), O-benzylhydroxylamine hydrochloride (205 mg, 1.28 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate (570 mg, 1.29 mmol). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed sequentially with 0.5 N hydrochloric acid solution, water, saturated sodium hydrogen carbonate solution and brine, dried over magnesium sulfate and concentrated under vacuum. The residue was chromatographed on silica gel using 20% hexane in ethyl acetate to afford 2-(R)-N-benzyloxy-2-[(4-methoxybenzenesulfonyl)(2- morpholin-4-yl-2-oxoethyl)amino]-3-methylbutyramide as a white foam, 510 mg (84%).
To a solution of 2-(R)-N-benzyloxy-2-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]-3-methylbutyramide (510 mg, 0.98 mmol) in methanol (50 mL) was added 5% palladium on activated carbon (120 mg). The mixture was agitated under 2 atmospheres hydrogen in a Parr shaker for 2 hours.
The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated leaving 2-(R)-N-hydroxy-2-[(-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]-3-methylbutyramide as a white solid, 418 mg (99%);1H NMR (CDCl3) : δ 10.3 (br s, 1H), 7.90 (br s, 1H, overlapped), 7.86 (d, J = 8.8 Hz, 2H, overlapped), 6.94 (d, J = 8.8 Hz, 2H), 4.39 (d, J = 17.1 Hz, 1H), 4.09 (d, J = 17.1, 1H), 3.84 (s, 3H), 3.80-3.48 (m, 9H), 2.20-1.95 (m, 1H), 0.82 (d, J = 6.5 Hz, 3H), 0.45 (d, J = 6.5 Hz, 3H); MS (LSIMS): m/z 430 (M+H).
EXAMPLE 2
2-(R)-N-Hydroxy-2-[(4-methoxybenzenesulfonyl) (3-morpholin-4-yl-3-oxopropyl)amino]-3-methylbutyramide
To a solution of N-(4-methoxybenzenesulfonyl)-D-valine benzyl ester (2.2 grams, 5.83 mmol) in dry dimethylformamide (40 mL) were added cesium carbonate (2.3 grams, 7.1 mmol) and 1- iodo-3-butene (1.3 grams, 7.1 mmol). The mixture was stirred at room temperature overnight and was then poured into water. The mixture was extracted twice with ether and the combined ether extracts were washed with brine, dried over magnesium sulfate and
concentrated under reduced pressure. The residue was taken up in 20% ethyl acetate/hexane; starting material N-(4-methoxybenzenesulfonyl)-D-valine benzyl ester (1.5 g) crystallized from the mixture and was recovered by filtration. The filtrate was concentrated under vacuum and the residue was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to provide 2-(R)-2-[but-3-enyl(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester as a clear oil,
404 mg (16%).
To a mixture of 2-(R)-2-[but-3-enyl(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (780 mg, 1.81 mmol) and ruthenium (III) chloride hydrate (10 mg, 0.048 mmol) in acetonitrile (6 mL), carbon tetrachloride (6 mL) and water (8 mL) was added sodium periodate (1.7 grams, 7.9 mmol). After stirring at room temperature for 2 hours, the mixture was diluted with methylene chloride and filtered through diatomaceous earth. The organic layer was separated, washed with dilute hydrochloric acid
solution and brine, dried over magnesium sulfate and concentrated to leave 2-(R)-2-[2-carboxyethyl(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester as an oil, 710 mg (87%).
Alternatively, the intermediate 2-(R)-2-[2-carboxyethyl(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester was prepared by the following higher yielding procedure:
N-(4-Methoxybenzenesulfonyl)-D-valine benzyl ester (18.8 grams, 49.8 mmol) was added to a suspension of sodium hydride (1.3 grams, 54 mmol) in dry
dimethylformamide (200 mL) and, after 1.5 hours, a solution of allyl bromide (4.7 mL, 54 mmol) was added. The resulting mixture was stirred overnight at room temperature and was then quenched by addition of saturated ammonium chloride solution. The
dimethylformamide was removed by evaporation under vacuum. The residue was taken up in ether and washed with water and brine. After drying over magnesium sulfate, ether was evaporated to leave an oil from which 2-(R)-2-[(4-methoxybenzenesulfonyl)prop-2- enylamino]-3-methylbutyric acid benzyl ester, a clear oil (18.1 grams, 87%), was isolated using flash chromatography on silica gel eluting with 10% ethyl acetate in hexane and then 20% ethyl acetate in hexane.
To a 1 M solution of borane/disulfide complex in methylene chloride (1.45 mL, 2.9 mmol) was added a solution of 2-(R)-2-[(4-methoxybenzenesulfonyl)prop-2-enylamino]-3-methylbutyric acid benzyl ester (3.6 grams, 8.6 mmol) in methylene chloride (8 mL). The solution was stirred at room temperature for 4 hours at which time more 1 M solution of borane/disulfide complex in methylene chloride (2.0 mL, 4.0 mmol) was added. The mixture was stirred at room temperature overnight and was then added dropwise to a mechanically stirred solution of chromium trioxide (5.1 grams, 51.6 mole) in acetic acid (31 mL) and water (3.5 mL) while keeping the internal temperature between -5°C. and
10°C. After stirring at room temperature overnight, the mixture was diluted with water and extracted with methylene chloride. The extract was washed with brine, dried (magnesium sulfate) and concentrated. The residue was chromatographed on silica gel eluting successively with chloroform and 2% methanol in
chloroform to afford 2-(R)-2-[2-carboxyethyl(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl as an oil (2.42 grams, 63%).
To a solution of 2-(R)-2-[2-carboxyethyl(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (710 mg, 1.58 mmol) in methylene chloride (15 mL) were added sequentially triethylamine (0.47 mL, 3.35 mmol), morpholine (0.15 mL, 1.72 mmol) and
(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (769 mg, 1.74 mmol). The mixture was stirred at room temperature overnight and then diluted with methylene chloride. The solution was washed with 0.5 N hydrochloric acid solution and brine, dried over magnesium sulfate and concentrated under vacuum. The solid residue was chromatographed on silica gel using 20% hexane in ethyl acetate affording 2-(R)-2-[(4-methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino]-3-methylbutyric acid benzyl ester as a clear oil, 725 mg (88%).
To a solution of 2-(R)-2-[(4-methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino]-3-methylbutyric acid benzyl ester (725 mg, 1.40 mmol) in ethanol (35 mL) was added 10%
palladium on activated carbon (50 mg). The mixture was agitated under 3 atmospheres hydrogen in a Parr shaker for 3 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated leaving 2-(R)-(2)-[(4-methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino]-3-methyl-butyric acid as a white solid, 540 mg (90%).
To a solution of 2-(R)-2-[(4-methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino]-3-methylbutyric acid (540 mg, 1.26 mmol) and 1-hydroxybenztriazole hydrate (205 mg, 1.33 mmol) in dry dimethylformamide (12 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (289 mg, 1.51 mmol). After stirring for 30 minutes, hydroxylamine hydrochloride (350 mg, 5.04 mmol) and then triethylamine (1.0 mL, 7.17 mmol) were added.
The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed sequentially with water, 0.5 N hydrochloric acid solution and brine. The solution was then dried over magnesium sulfate and concentrated under vacuum to leave a white foam. The material was dissolved in toluene, filtered and concentrated. The residue was triturated with ether to afford 2-(R)-N-hydroxy-2[(4-methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino]-3-methylbutyramide as a solid, 200 mg (36%);1H NMR (CDCl3) : δ 9.35 (br s, 1H), 7.73 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 3.86 (s, 3H), 3.83-3.73 (m, 1H), 3.70-3.52 (m, 7H), 3.46-3.43 (m, 2H), 3.41-3.29 (m, 1H), 2.92-2.69 (m, 2H), 2.30-2.17 (m, 1H), 0.84 (d, J = 6.5 Hz, 3H), 0.41 (d, J = 6.5 Hz, 3H); MS (particle beam): m/z 444 (M+H) , 428, 383, 329; HRMS calculated for C19H30N3O7S (M+H): 444.1804,
Found: 464.1818.
The title compounds of Examples 3-6 were prepared by a method analogous to that described in Example 2 using 2-(R)-2-[2-carboxyethyl(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester as the starting material which is coupled with the amine indicated.
EXAMPLE 3
2-(R)-2-[(2-Benzylcarbamoylethyl)(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyramide
Coupled with benzylamine;1H NMR (DMSO-d6) : δ 10.72 (s, 1H), 8.89 (s, 1H), 8.39 (m, 1H), 7.74 (d, J = 9.0 Hz, 2H), 7.32-7.21 (m, 5H), 7.05 (d, J = 9.0 Hz, 2H), 4.21 (d, J = 5.9 Hz, 2H), 4.02-3.87 (m, 1H), 3.82 (s, 3H), 3.63 (d, J = 10.8 Hz, 1H), 3.29-3.17 (m, 1H), 2.71-2.57 (m, 1H), 2.52-2.40 (m, 1H), 2.06-1.94 (m, 1H), 0.77 (d, J = 6.6 Hz, 3H), 0.74 (d, J = 6.5 Hz, 3H); MS (LSIMS) : m/z 464 (M+H); HRMS calculated for C22H30N3O6S (M+H): 464.1855. Found: 464.1832.
EXAMPLE 4
2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl) (2-[(pyridin-3-ylmethyl)carbamoyl]ethyl)amino)-3-methylbutyramide
Coupled with 3-pyridylmethylamine:1H NMR (DMSO-d6): δ 10.72 (s, 1H), 8.89 (s, 1H), 8.49-8.42 (m, 3H), 7.73 (d, J = 8.9 Hz, 2H), 7.63-7.60 (m, 1H), 7.32 (dd, J = 4.8, 7.8 Hz, 1H), 7.05 (d, J = 8.9 Hz, 2H), 4.23 (d, J = 5.8 Hz, 2H), 4.00-3.88 (m, 1H), 3.81 (s, 3H), 3.62 (d, J = 10.8 Hz, 1H), 3.27-3.17 (m, 1H), 2.69-2.58 (m, 1H), 2.52-2.41 (m, 1H), 2.07-1.94 (m, 1H), 0.76 (d, J = 6.5 Hz, 3H), 0.72 (d, J = 6.4 Hz, 3H); MS (LSIMS) : m/z 465 (M+H). EXAMPLE 5
2-(R)-N-Hydroxy-2-([4-methoxybenzenesulfonyl] [2-(methylpyridin-3-ylmethylcarbamoyl)ethyl]amino)-3-methylbutyramide
Coupled with 3-(N-methylaminomethyl)pyridine:
1H NMR (DMSO-d6): δ 10.75 (br s, 1H), 8.92 (s, 1H), 8.52-8.29 (m, 2H), 7.75 (d, J = 8.8 Hz, 1.4 H), 7.67 (d, J = 8.8 Hz, 0.6 H), 7.62-7.58 (m, 1H), 7.42-7.32 (m, 1H), 7.06 (d, J = 8.8 Hz, 1.4 H), 7.01 (d, J = 8.8 Hz, 0.6 H), 4.55-4.41 (m, 2H), 3.94-3.82 (m, 1H), 3.81 (s, 2.1 H), 3.80 (s, 0.9 H), 3.68-3.60 (m, 1H), 3.33-3.19 (m, 1H), 2.90-2.50 (m, 2H), 2.88 (s, 2.1 H
overlapped), 2.79 (s, 0.9 H), 2.05-1.80 (m, 1H),
0.79-0.63 (m, 6H) : MS (thermospray) : m/z 479
(M+H), 364.
EXAMPLE 6
4-(3-[(1-(R)-1-Hydroxycarbamoyl-2-methylpropyl)(4-methoxybenzenesulfonyl)amino]propionyl) piperazine-1-carboxylic acid, tert-butyl ester
Coupled with tert-butyl-1-piperazinecarboxylate :1H NMR (DMSO-d6): δ 10.77 (br s, 1H), 8.93 (s, 1H), 7.74 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 8.9 Hz, 2H), 3.90-3.80 (m, 1H), 3.82 (s, 3H, overlapped), 3.64 (d, J = 10.8 Hz, 1H), 3.60-3.16 (m, 9H), 2.80-2.71 (m, 1H), 2.59-2.47 (m, 1H), 2.03-1.91 (m, 1H), 1.39 (s, 9H), 0.77 (d, J = 6.5 Hz, 3H), 0.71 (d, J = 6.5, 3H); MS (thermospray) : m/z 543 (M+H), 443, 382, 328.
EXAMPLE 7
2-(R)-N-Hydroxy-2-[(4-methoxybenzenesulfonyl)
(3-oxo-3-piperazin-1-ylpropyl)amino]-3-methylbutyramide hydrocholoride
A solution of 4-(3-[(1-(R)-1- hydroxycarbamoyl-2-methylpropyl)(4- methoxybenzenesulfonyl)amino]propionyl)piperazine-1- carboxylic acid, tert-butylester [Example 6] (430 mg, 0.79 mmol) in methylene chloride (11 mL) was cooled to 0°C. Hydrogen chloride gas was then bubbled through the solution for about 0.5 minute. The solution was allowed to warm to room temperature with stirring over 1 hour. Volatiles were removed by evaporation and the residue was filtered washing with methylene chloride to collect solid 2-(R)-N-hydroxy-2-[(4-methoxybenzenesulfonyl)(3-oxo-3-piperazin-1-ylpropyl)amino]-3-methylbutyramide hydrochloride, 375 mg (99%).1H NMR (DMSO-d6): δ 10.78 (br s, 1H), 9.16 (br s, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 3.82 (s, 3H), 3.62 (br s, 4H), 3.38-3.18 (m, 1H), 3.16-3.07 (br s, 2H), 3.07-2.98 (br s, 2H), 2.83-2.73 (m, 1H), 2.65-2.53 (m, 1H), 2.06-1.90 (m, 1H), 0.76 (d, J = 6.5 Hz, 3H), 0.72 (d, J = 6.5 Hz, 3H). A broad water peak between δ 4.0 and 3.5 obscured some signals from this compound; MS (thermospray) : m/z 443 (M+H), 382, 328.
EXAMPLE 8
2-(R)-2-[(Benzylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyramide
To a solution of 2-(R)-2-[carboxymethyl(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (example 1) (905 mg, 2.08 mmol) in
methylene chloride (18 mL) were added sequentially triethylamine (0.72 mL, 5.14 mmol), benzylamine (0.25 mL, 2.29 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.01 grams, 2.28 mmol). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed with 0.5 N hydrochloric acid solution and brine, dried over magnesium sulfate and concentrated under vacuum. The residue was chromatographed on silica gel using a
2:5:16 ratio of methylene chloride/ethyl acetate/hexane affording 2-(R)-2-[(benzylcarbamoylmethyl)(4- methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester as a clear oil, 933 mg (86%).
To a solution of 2-(R)-2- [(benzylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (933 mg, 1.17 mmol) in ethanol (50 mL) was added 10% palladium on activated carbon (85 mg). The mixture was agitated under 3 atmospheres hydrogen in a Parr shaker for 4 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was
evaporated leaving 2-(R)-2-[(benzylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid as a white foam, 755 mg (98%).
To a solution of 2-(R)-2- [(benzylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid (655 mg, 1.51 mmol) and 1-hydroxybenztriazole hydrate (224 mg, 1.46 mmol) in dry dimethylformamide (15 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (316 mg, 1.65 mmol). After stirring for 30 minutes, hydroxylamine hydrochloride (416 mg, 6.0 mmol) and then N-methylmorpholine (0.99 mL, 9.0 mmol) were added. The mixture was stirred at room
temperature overnight and then diluted with ethyl acetate. The solution was washed sequentially with water, 0.5 N hydrochloric acid solution and brine. The solution was then dried over magnesium sulfate and concentrated under vacuum to leave a white foam which was chromatographed on silica gel eluting with ethyl acetate to afford 2-(R)-2-[(benzylcarbamoylmethyl)(4-methoxybenzene-sulfonyl)amino]-N-hydroxy-3-methylbutyramide as a white foam, 570 mg (84%);1H NMR (DMSO-d6): δ 10.75 (br s, 1H), 8.90 (s, 1H), 8.47 (m, 1H), 7.85 (d, J - 8.9 Hz, 2H), 7.83-7.19 (m, 5H), 7.04 (d, J = 8.9 Hz, 2H), 4.37 (d, J = 11.4 Hz, 1H), 4.28 (d, J = 5.9 Hz, 2H), 3.89 (d, J = 11.4 Hz, 1H), 3.82
(s, 3H), 3.45 (d, J = 10.3 Hz, 1H), 1.90-1.79 (m, 1H), 0.73 (d, J = 6.3 Hz, 6H); MS (LSIMS): m/z 450 (M+H). EXAMPLE 9
2-(R)-2-[(Benzylmethylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyramide
To a solution of 2-(R)-2-[carboxymethyl(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (Example 1) (1.05 grams, 2.41 mmol) in methylene chloride (20 mL) were added sequentially triethylamine (0.84 mL, 6.0 mmol), N-benzylmethylamine (0.34 mL, 2.63 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino) phosphonium
hexafluorophosphate (1.17 grams, 2.69 mmol). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed with 0.5 N hydrochloric acid solution and brine, dried over magnesium sulfate and concentrated under vacuum. The residue was chromatographed on silica gel using 35% ethyl acetate in hexane (plus a email amount of methylene chloride to load the sample on the column) affording 2-(R)-2-[benzylmethylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester as a clear oil, 1.14 grams (88%).
To a solution of 2-(R)-2- [(benzylmethylcarbamoylmethyl)(4- methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (1.14 grams, 2.12 mmol) in ethanol (100 mL) was added 10% palladium on activated carbon (400 mg). The mixture was agitated under 3 atmospheres hydrogen in a Parr shaker for 3 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated leaving 2-(R)-2- [(benzylmethylcarbamoylmethyl)(4- methoxybenzenesulfonyl)amino]-3-methylbutyric acid as a white foam, 902 mg (95%).
To a solution of 2-(R)-2- [(benzylmethylcarbamoylmethyl)(4methoxybenzenesulfonyl)amino]-3-methylbutyric acid (902 mg, 2.01 mmol) in methylene chloride (20 mL) were added sequentially triethylamine (0.90 mL, 6.42 mmol), O-allylhydroxylamine hydrochloride (242 mg, 2.21 mmol) and (benzotriazol-1-yloxy)tris- (dimethylamino) phosphonium hexafluorophosphate (978 mg, 2.21 mmol). The mixture was stirred at room
temperature overnight and then diluted with ethyl acetate. The solution was washed with 0.5 N
hydrochloric acid solution and brine, dried over magnesium sulfate and concentrated under vacuum. The residue was chromatographed on silica gel using 40% hexane in ethyl acetate to afford 2-(R)-N-allyloxy-2- [(benzylmethylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino]-3-methylbutyramide as an oil, 1.008 grams (100%).
To a solution of 2-(R)-N-allyloxy-2- [(benzylmethyl-carbamoylmethyl)(4-methoxybenzenesulfonyl)amino]-3-methylbutyramide (500 mg, 0.99 mmol) in methylene chloride (40 mL) was added bis (triphenylphosphine) palladium (II) chloride (280 mg, 0.4 mmol) and then, dropwise, tributyltinhydride (0.43 mL, 2.2 mmol). The solution was stirred at room temperature for 1 hour, diluted with methylene
chloride, washed with 1 N hydrochloric acid solution, dried over magnesium sulfate and concentrated. The residue was taken up in ethyl acetate and filtered to remove a solid. After concentration, the filtrate was chromatographed on silica gel eluting with chloroform and then 2% methanol in chloroform to afford 2-(R)-2- [(benzylmethylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyramide as a white solid (340 mg, 74%).1H NMR (DMSO-d6): δ 10.66 (br s, 1H), 8.87 (br s, 0.6 H), 8.84 (s, 0.4 H), 7.91 (d, J = 8.9 Hz, 1.2 H), 7.78 (d, J = 8.9 Hz, 0.8 H), 7.43-7.21 (m, 5H), 7.05 (d, J = 8.9 Hz, 1.2 H), 7.00 (d, J = 8.9 Hz, 0.8 H) 4.72 (d, J = 17.7 Hz, 0.4 H), 4.70 (d, J = 17.7 Hz, 0.6 H), 4.59-4.42 (m, 1H), 4.25 (d, J = 17.8 Hz, 0.6H), 4.07 (d, J = 17.7 Hz, 0.4H), 3.82 (s, 3H), 3.46-3.40 (m, 1H), 2.91 (s, 1.8H), 2.83 (s, 1.2 H), 1.92-1.70 (m, 1H), 0.75-0.69 (m, 6H); MS (thermospray): m/z 464 (M+H), 307, 239.
The title compounds of Examples 10-11 were prepared by a method analogous to that described in Example 9 using 2-(R)-2-[carboxymethyl(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (Example 1) as the starting material which is coupled with the amine indicated.
EXAMPLE 10
2-(R)-N-Hydroxy-2-([4-methoxybenzenesulfonyl]-[(2-morpholin-4-ylethylcarbamoyl)methyl]amino)-3-methylbutyramide
Coupled with 4- (2-aminoethyl)morpholine:1H
NMR (DMSO-d6): δ 10.74 (br s, 1H), 8.90 (br s, 1H), 7.84 (br s, 1H, overlapped), 7.84 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 4.33 (d, J = 17.5 Hz, 1H), 3.83 (s, 3H), 3.78 (d, J = 17.5 Hz, 1H), 3.57-3.54 (m, 4H), 3.49 (d, J = 10.2 Hz, 1H), 3.28-3.06 (m, 2H), 2.34-2.30 (m, 6H), 1.93-1.77 (m, 1H), 0.77-0.74
(m, 6H).
EXAMPLE 11
2-(R)-N-Hydroxy-2-[(4-methoxybenzenesulfonyl)(2-oxo-2-pyrrolidin-1-ylethyl)amino]-3-methylbutyramide
Coupled with pyrrolidine: H NMR (CD3OD) : δ 7.90 (d, J = 8.9 Hz, 2H), 7.04 (d, J = 8.9 Hz, 2H), 4.50 (d, J = 17.6 Hz, 1H), 4.15 (d, J = 17.6 Hz, 1H), 3.87 (s, 3H), 3.56-3.39 (m, 5H), 2.07-1.82 (m, 5H),
0.83 (d, J = 6.6 Hz, 3H), 0.73 (d, J = 6.6 Hz, 3H); MS (thermospray) : m/z 414 (M+1); HRMS calculated for C18H28N3O6S (M+H): 414.1699. Found 414.1703. EXAMPLE 12
2-[Dimethylcarbamoylmethyl(4-methoxybenzenesulfonγl)amino]-N-hydroxy-3-methylbutyramide
A solution of 2-(R)-2-[carboxymethyl(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (Example 1) (1.89 grams, 4.34 mmol) in thionyl chloride (25 mL) was heated at reflux for 1 hour. After cooling, the excess thionyl chloride was evaporated. The residue was taken up in methylene chloride (50 mL) and the solution was cooled in an ice bath. Dimethylamine gas was slowly bubbled through the solution for 1 hour. After evaporation of the solvent, the residue was taken up in ethyl acetate, washed with I N hydrochloric acid solution, water and brine, dried over magnesium sulfate and concentrated to leave dimethylcarbamoylmethyl(4-methoxybenzenesulfonyl)amino-3-methylbutyric acid benzyl ester as an oil, 1.77 grams (88%).
To a solution of dimethylcarbamoylmethyl (4-methoxybenzenesulfonyl)amino-3-methylbutyric acid benzyl ester (1.77 grams, 3.83 mmol) in ethanol (100 mL) was added 10% palladium on activated carbon (644 mg). The mixture was agitated under 3 atmospheres hydrogen in a Parr shaker for 1.5 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated leaving dimethylcarbamoylmethyl(4-methoxybenzenesulfonyl)amino-3- methylbutyric acid as a white foam, 1.42 grams (100%).
To a solution of dimethylcarbamoylmethyl(4- methoxybenzenesulfonyl)amino-3-methylbutyric acid (1.42 grams, 3.81 mmol) and 1-hydroxybenztriazole hydrate (687 mg, 4.48 mmol) in dry dimethylformamide (7 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (974 mg, 5.08 mmol). After stirring for 30 minutes, hydroxylamine hydrochloride (1.17 grams, 16.8 mmol) and then N-methylmorpholine (2.8 mL, 25.5 mmol) were added. The mixture was stirred at room temperature overnight and then concentrated under vacuum. The residue was taken up in ethyl acetate and the resulting solution was washed sequentially with water, 0.5 N hydrochloric acid solution and brine. The solution was then dried over magnesium sulfate and concentrated under vacuum to leave an oil which was chromatographed on silica gel eluting successively with ethyl acetate, 5% methanol in chloroform and 10% methanol in chloroform to afford 2-[dimethylcarbamoylmethyl(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyramide as a white solid, 390 mg (26%).1H NMR (DMSO-d6): δ 10.70 (br s, 1H), 8.89 (s, 1H), 7.80 (d, J = 8.9 Hz, 2H), 7.10 (d, J = 8.9 Hz, 2H), 4.62 (d, J - 17.7 Hz, 1H), 4.14 (d, J = 17.7 Hz, 1H), 3.84 (s, 3H), 3.40 (d, J = 10.4 Hz, 1H), 2.97 (s, 3H), 2.82 (s, 3H), 1.88-1.72 (m, 1H), 0.72 (d, J = 6.5 Hz, 6H); MS (thermospray): m/z 388 (M+1); HRMS
calculated for C16H26N3O6S (M+H): 388.1542 Found:
388.1592.
EXAMPLE 13
2-(R)-2-N-Hydroxy-2-((4-methoxybenzenesulfonyl)([(pyridin-3-ylmethyl)carbamoyl)methyl)amino)-3-methylbutyramide
2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)([(pyridin-3-ylmethyl)carbamoyl]methyl)amino)-3-methylbutyramide was prepared by a procedure similar to that of Example 12 starting with 2-(R)-2-[carboxymethyl(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (Example 1) and coupling this to 3-pyridylmethylamine via the acid chloride.1H NMR
(CD3OD) : δ 8.55-8.53 (m, 1H), 8.43-8.44 (m, 1H), 7.90- 7.82 (m, 1H, overlapped), 7.86 (d, J = 8.9 Hz, 2H), 7.40 (dd, J = 4.8, 7.8 Hz, 1H), 7.04 (d, J = 8.9 Hz, 2H), 4.50 (d, J = 17.5 Hz, 1H), 4.39 (d, J = 17.5 Hz, 1H), 4.32 (d, J = 17.7 Hz, 1H), 4.02 (d, J = 17.7 Hz, 1H), 3.87 (s, 3H), 3.60 (d, J = 10.3 Hz, 1H), 2.08-1.93 (m, 1H), 0.85 (d, J = 6.5 Hz, 3H), 0.70 (d, J = 6.5 Hz, 3H); MS (thermospray) : m/z 451 (M+H), 336, 320.
EXAMPLE 14
N-Hydroxy-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]acetamide
To a solution of iminoacetic acid disodium salt monohydrate (5.0 grams, 25.6 mmol) in dioxane (50 ml) and water (50 ml) was added triethylamine (5.3 ml, 38 mmol) followed by 4-methoxybenzenesulfonyl chloride (5.8 grams, 28.0 mmol). The mixture was stirred overnight at room temperature and diluted with
methylene chloride. The solution was washed with 1 N hydrochloric acid solution, water and brine, dried over magnesium sulfate and concentrated under vacuum leaving [carboxymethyl (4-methoxybenzenesulfonyl) amino] acetic acid as a white solid, 3.83 grams (49%).
[Carboxymethyl(4-methoxybenzenesulfonyl)amino]acetic acid (0.5 grams, 1.65 mmol) in acetic anhydride (15 mL) was dissolved in acetic anhydride by gentle warming. The resulting solution was stirred at room temperature overnight.
The acetic anhydride was removed by evaporation under vacuum; the residue was dissolved in methylene chloride and morpholine (0.16 mL, 1.82 mmol) was added. The mixture was stirred overnight at room temperature and then concentrated under vacuum. The residue was dissolved in ethyl acetate, washed with 1 N
hydrochloric acid solution, water and brine, dried over magnesium sulfate and concentrated to afford [(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2- oxoethyl)amino]acetic acid as an oil, 0.33 grams (54%).
To a solution of [(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)- amino]acetic acid (0.33 grams, 0.89 mmol) in methylene chloride (10 mL) were added sequentially triethylamine (0.43 mL, 3.1 mmol), O-benzylhydroxylamine hydrochloride (0.15 grams, 0.94 mmol) and
(benzotriazol-1-yloxy)tris(dimethylajaino) phosphonium hexafluorophosphate (0.43 grams, 0.97 mmol). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed sequentially with 0.5 N hydrochloric acid solution, water and brine, dried over magnesium sulfate and concentrated under vacuum. The residue was
chromatographed on silica gel using ethyl acetate to afford N-benzyloxy-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]acetamide as a white solid, 0.33 grams (78%).
To a solution of N-benzyloxy-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]acetamide (0.33 grams, 0.69 mmol) in methanol (35 mL) was added 5% palladium on activated carbon (85 mg). The mixture was agitated under 2 atmospheres hydrogen in a Parr shaker for 1.5 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated.
The residue was chromatographed on silica gel eluting with 5% methanol in methylene chloride to afford N-methoxy-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]acetamide as a white solid, 65 mg (24%);1H NMR (CD3OD) : δ 7.82 (d, J = 9.0 Hz, 2H), 7.08 (d, J = 9.0 Hz, 2H), 4.24 (s, 2H), 3.88 (s, 3H), 3.84 (s, 2H), 3.68-3.64 (m, 4H), 3.58-3.50 (m, 4H); MS
(thermoepray) : m/z 388 (M+1), 387 (M); HRMS calculated for C16H22N3O7S (M+H): 388.11788 Found 338.1180.
The title compounds of Examples 15-16 were prepared by a method analogous to that described in Example 14 using [carboxymethyl(4- methoxybenzenesulfonyl)amino]acetic acid as the
starting material which, after treatment with acetic anhydride, is coupled with the amine indicated. EXAMPLE 15
N-Hydroxy-[(4-methoxybenzenesulfonyl)(2-oxo-2-pyrrolidin-1-ylethyl)amino]acetamide
Coupled with pyrrolidine:1H NMR (DMSO-d6) : δ 11.26 (br s, 1H), 8.89 (s, 1H), 7.81 (d, J = 8.9 Hz, 2H), 7.10 (d, J = 8.9 Hz, 2H), 4.09 (s, 2H), 3.85 (s, 3H), 3.74 (s, 2H), 3.45-3.25 (m, 4H), 1.93-1.72
(m, 4H); MS (thermospray) : m/z 372 (M+1) : Analysis calculated for C15H21N3O6S: C, 48.51; H, 5.70; N, 11.31. Found: C, 48.51; H, 5.82; N, 11.24.
EXAMPLE 16
2 -[Dimethylcarbamoylmethyl(4-methoxybenzenesulforyl)amino]-N-hydroxyacetamide
Coupled with dimethylamine : mp: 170°C.
(dec);1H NMR (DMSO-d6): δ 10.69 (br s, 1H), 8.88 (s, 1H), 7.91 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 8.9 Hz, 2H), 4.19 (s, 2H), 3.85 (s, 3H), 3.73 (B, 2H), 2.94 (s, 3H), 2.84 (s, 3H); MS (thermospray): m/z 346
(M+1); Analysis calculated for C13H19N3O6S: C, 45.21; H, 5.55 N, 12.17. Found: C, 44.93, H, 5.61; N, 12.03.
EXAMPLE 17
2-(R)-2-[(2-Carbamoylethyl)(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyramide
To a solution of 2-(R)-2-[(2-carboxyethyl(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (example 2) (900 mg., 2.0 mmol) in
methylene chloride (10 mL) was added thionyl chloride (0.16 mL, 2.2 mmol). The reaction mixture was stirred for 1.5 hours at room temperature and then concentrated in vacuo. After dissolving the residue in methylene chloride (10 mL), ammonia gas was bubbled through the solution for 0.5 minutes. The solution was stirred at room temperature overnight and was concentrated under vacuum. Flash chromatography of the residue on silica gel eluting with 2% methanol in chloroform provided 2- (R)-2-[(2-carbamoylethyl)(4- methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyric acid benzyl ester as a clear oil (275 mg, 31%).
To a solution of 2-(R)-2-[(2-carbamoylethyl)(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyric acid benzyl ester (275 mg, 0.61 mmol) in ethanol (15 mL) was added 10% palladium on activated carbon (30 mg). The mixture was agitated under 3 atmospheres hydrogen in a Parr shaker for 5 hours. The catalyst was removed by filtration through diatomaceous earth and the solvent was evaporated leaving 2-(R)-2-[(2-carbamoylethyl)(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyric acid as a white foam, 211 mg (96%).
To a solution of 2-(R)-2-[(2-carbamoylethyl)(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyric acid (205 mg, 0.57 mmol) and 1-hydroxybenztriazole hydrate (85 mg, 0.55 mmol) in dry dimethylformamide (5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (120 mg, 0.63 mmol). After stirring for 30 minutes, hydroxylamine hydrochloride (158 mg, 2.3 mmol) and then N-methylmorpholint (0.37 mL, 3.4 mmol) were added. The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed with water and brine. The solution was then dried over magnesium sulfate and concentrated under vacuum to leave an oil which was chromatographed on silica gel eluting with 2% methanol in chloroform to afford 2-(R)-2-[(2-carbamoylethyl)(4- methoxybenzenesulfonyl)amino]-N-hydroxy-3- methylbutyramide as a white solid, 45 mg (21%);1H NMR (DMSO-d6): δ 10.74 (br s, 1H), 8.91 (br s, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.33 (br s, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.79 (br s, 1H), 3.93-3.82 (m, 1H,
overlapped), 3.83 (s, 3H), 3.64 (d, J = 10.7 Hz, 1H), 3.25-3.12 (m, 1H), 2.62-2.48 (m, 1H), 2.42-2.30 (m, 1H), 2.06-1.94 (m, 1H), 0.79 (d, J = 6.6 Hz, 3H), 0.76 (d, J = 6 . 6 Hz , 3H); MS ( thermospray) : m/z 374 (M+H).
EXAMPLE 18
2-(R)-2-[(2-tert-Butoxycarbonylethyl)(4-methoxybenzenesulforyl)-amino]-N-hydroxy-3-methylbutyramide
A solution of N,N-dimethylformamide di-tert-butyl acetal (1.9 mL, 7.9 mmol) in toluene (15 mL) was added dropwise to a solution of 2-(R)-2-[(2-carboxyethyl(4-methoxybenzenesulfonyl)amino]-3¬methylbutyric acid benzyl ester (example 2) 900 mg, 2.0 mmol) in toluene at 80 °C. After heating for 2 hours at 80°C, the mixture was cooled and concentrated to leave an amber oil which was chromatographed on silica gel eluting with chloroform to afford (2-(R)-2-[(2-tert-butoxycarbonylethyl)(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester as an oil,
3.75 mg (37%).
To a solution of 2-(R)-2-[(2-tert-butoxycarbonylethyl)(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (370 mg, 0.73 mmol) in ethanol (20 mL) was added 10% palladium on activated carbon (40 mg). The mixture was agitated under 3 atmospheres hydrogen in a Parr shaker for 5 hours. The catalyst was removed by filtration through diatomaceous earth and the solvent was evaporated leaving 2-(R)-2- [(2-tert-butoxycarbonylethyl)(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid as a white foam, 30 mg (100%).
To a solution of 2-(R)-2-[(2-tert- butoxycarbonylethyl)(4-methoxybenzenesulfonyl)amino]-3- methylbutyric acid (303 mg, 0.73 mmol) and 1- hydroxybenztriazole hydrate (108 xng, 0.70 mmol) in dry dimethylformamide (10 mL) was added 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (153 mg, 0.80 mmol). After stirring for 45 minutes, hydroxylamine hydrochloride (203 mg, 2.9 mmol) and then N-methylmorpholine (0.48 mL, 4.4 mmol) were added. The mixture was stirred at room temperature overnight and then concentrated under vacuum. The residue was chromatographed on silica gel eluting with 2% methanol in chloroform and again with 10% ethyl acetate in hexane to afford 2-(R)-2-[(2-tert-butoxycarbonylethyl)(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyramide as a white foam, 135 mg (43%);1H NMR (DMSO-d6): δ 10.77 (br s 1H), 7.74 (d, J = 8.9 Hz, 2H), 7.08 (d, J = 8.9 Hz, 2H), 3.93-3.82 (m, 1H, overlapped), 3.83 (s, 3H), 3.64 (d, J = 10.8 Hz, 1H), 3.26-3.14 (m, 1H), 2.70-2.60 (m, 1H), 2.50-2.38 (m, 1H), 2.04-1.91 (m, 1H), 1.38 (s, 9H), 0.78 (d, J = 6.5 Hz, 3H), 0.72 (d, J = 6.5 Hz, 3H); MS
(thermospray) : m/z 431 (M+H), 375, 314.
EXAMPLE 19
2-(R)-2-[2-Carboxyethyl)(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyramide
To a solution of 2-(R)-2-[2-tert-butoxycarbonylethyl)(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyramide (example 18) (100 mg, 0.23 mmol) in methylene chloride (1 mL) at 0°C. was added trifluoroacetic acid (1 mL). The mixture was allowed to warm to room temperature while stirring overnight. After evaporation of the trifluoroacetic acid and methylene chloride, the residue was chromatographed on silica gel eluting with 5% methanol in chloroform.
Concentration of the appropriate fractions afforded 2- (R)-2-[2-carboxyethyl(4-methoxybenzenesulfonyl)amino]- N-hydroxy-3-methylbutyramide as a white solid, 35 mg
(41%).1H NMR (DMSO-d6): δ 10.79 (br S,1H), 8.97 (br s, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 3.95-3.82 (m, 1H, overlapped), 3.84 (s, 3H), 3.66 (d, J = 10.8 Hz, 1H), 3.30-3.20 (m, 1H), 2.73-2.62 (m, 1H), 2.50-2.40 (m, 1H), 2.07-1.94 (m, 1H), 0.80 (d, J = 6.5 Hz, 3H), 0.74 (d, J = 6.5 Hz, 3H); MS
(thermospray): m/z 375 (M+H), 314.
Claims
C L A I M S
A compound of the formula
or the pharmaceutically acceptable salts thereof, wherein
n is 1 to 6;
X is hydroxy, (C1-C6) alkoxy or NRXR2 wherein R1 and R2 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, piperidyl,
(C1-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C5- C9)heteroarylpiperidyl, (C6-C10)aryl (C1- C6)alkylpiperidyl, (C5-C9)heteroaryl (C1-C6)alkylpiperidyl, (C1-C6)acylpiperidyl, (C6-C10)aryl,
(C5-C9)heteroaryl, (C6-C10)aryl (C1-C6)alkyl, (C5- C9)heteroaryl(C1-C6)alkyl, (C6-C10)aryl(C8-C10)aryl,
(C6-C10)aryl (C6-C10)aryl(C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, R5(C2- C6)alkyl, (C1-C5)alkyl(CHR5)(C1-C6)alkyl wherein R5 is hydroxy, (C1-C6)acyloxy, (C1-C6)alkoxy, piperazino,
(C1-C6)acylamino, (C1-C6)alkylthio, (C6-C10)arylthio,
(C1-C6)alkylsulfinyl, (C6-C10)arylsulfinyl, (C1-C6)alkylsulfoxyl, (C6-C10)arylsulfoxyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)acylpiperazino, (C1-C6)alkylpiperazino, (C6- C10)aryl(C1-C6)alkylpiperazino, (C5-C9)heteroaryl (C1-C6)alkylpiperazino, morpholino, thiomorpholino, piperidino or pyrrolidino; R6(C1-C6)alkyl, (C1- C5)alkyl(CHR6)(C1-C6)alkyl wherein R6 is piperidyl,
(C1-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C6- C10)aryl(C1-C6)alkylpiperidyl, (C5- C9)heteroarylpiperidyl or (C5-C9)heteroaryl(C1-C6)alkylpiperidyl; and CH(R7)COR8 wherein R7 is
hydrogen, (C1-C6)alkyl, (C6-C10)aryl (C1-C6)alkyl, (C5-C9)heteroaryl(C1-C6)alkyl, (C1-C6)alkylthio (C1-C6)alkyl, (C6-C10)arylthio(C1-C6)alkyl, (C1-C6)alkylsulfinyl(C1-C6)alkyl, (C8-C10)arylsulfinyl (C1-C6)alkyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C6-C10)arylsulfonyl(C1-C6)alkyl, hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, (C1-C6 ) alkylamino(C1-C6)alkyl, ((C1-C6)alkylamino)2(C1-C6)alkyl, R9R10NCO(C1-C6)alkyl or R9OCO(C1-C6)alkyl wherein R9 and R1 are each
independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl and
(C5-C9)heteroaryl(C1-C6)alkyl; and R8 is R11O or
R11R12N wherein R11 and R12 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl and (C5-C9)heteroaryl(C1-C6)alkyl;
or R1 and R2, or R9 and R10, or R11 and R12 may be taken together to form an azetidinyl,
pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, (C1-C6)acylpiperazinyl, (C1-C6)alkylpiperazinyl, (C6-C10)arylpiperazinyl, (C5- C9)heteroarylpiperazinyl or a bridged diazabicycloalkyl ring selected from the group consisting of
wherein r is 1, 2 or 3 ;
m is 1 or 2;
p is 0 or 1; and
Q is hydrogen, (C1-C3)alkyl or (C1-C6)acyl;
R3 and R4 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, trifluoromethyl, trifluoromethyl (C1-C6)alkyl, (C1-C6)alkyl (difluoromethylene), (C1- C3)alkyl(difluoromethylene)(C1-C3)alkyl, (C6-C10)aryl, (C5-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C5-C9)heteroaryl(C1-C6)alkyl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl,
hydroxy(C1-C6)alkyl, (C1-C6)acyloxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, piperazinyl(C1-C6)alkyl, (C1-C6)acylamino(C1-C6)alkyl, piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)aryl(C1-C6)alkoxy(C1-C6)alkyl, (C5-C9)heteroaryl(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkylthiotC1-C6)alkyl, (C6-C10)arylthio(C1-C6)alkyl, (C1-C6)alkylsulfinyl(C1-C6)alkyl, (C6-C10)arylsulfinyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C6-C10)arylsulfonyl(C1-C6)alkyl, amino (C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkylamino)2(C1-C6)alkyl, R13CO(C1-C6)alkyl wherein
R13 is R20O or R20R21N wherein R20 and R21 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl or (C5-C9)heteroaryl(C1-C6)alkyl; or R14(C1-C6)alkyl wherein R14 is (C1-C6)acylpiperazino, (C6- C10)arylpiperazino, (C5-C9)heteroarylpiperazino, (C1-C6)alkylpiperazino, (C6-C10)aryl(C1-C6)alkylpiperazino, (C5-C9)heteroaryl (C1-C6)alkylpiperazino, morpholino,thiomorpholino, piperidino, pyrrolidino, piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C5-C9)heteroarylpiperidyl, (C6-C10)aryl(C1-C6)alkylpiperidyl, (C5-C9)heteroaryl(C1-C6)alkylpiperidyl or (C1-C6)acylpiperidyl;
or R3 and R4, or R20 and R21 may be taken together to form a (C3-C6)cycloalkyl, oxacyclohexyl, thiocyclohexyl, indanyl or tetralinyl ring or a group of the formula
o R15
wherein R15 is hydrogen, (C1-C6)acyl, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C5-C9)heteroaryl(C1-C6)alkyl or (C1-C6)alkylsulfonyl; and
Ar is (C6-C10)aryl, (C5-C9)heteroaryl, (C1-C6)alkyl(C6-C10)aryl, (C1-C6)alkoxy(C6-C10)aryl, ((C1-C6)alkoxy)2(C6-C10)aryl, (C6-C10)aryloxy(C6-C10)aryl, (C5-C9)heteroaryloxy(C6-C10)aryl, (C1-C6)alkyl(C5- C9)heteroaryl, (C1-C6)alkoxy(C5-C9)heteroaryl, ((C1-C6)alkoxy)2(C5-C9)heteroaryl, (C6-C10)aryloxy(C5- C9)heteroaryl, (C5-C9)heteroaryloxy(C5-C9)heteroaryl;
with the proviso that when either R1 or R2 is CH(R7)COR8 wherein R7 and R8 are as defined above, the other of R1 or R2 is hydrogen, (C1-C6)alkyl or benzyl.
2. A compound according to claim 1, wherein n is 2.
3. Α compound according to claim 1, wherein Ar is 4-methoxyphenyl or 4-phenoxyphenyl.
4. A compound according to claim 1, 2 or 3, wherein either R3 or R4 is not hydrogen.
5. A compound according to claim 1, wherein n is 1 and either R1 or R2 is hydrogen.
6. A compound according to claim 4, wherein X is hydroxy, Ar is 4-methoxyphenyl or 4-phenoxyphenyl.
7. A compound according to claim 4, wherein X is alkoxy, Ar is 4-methoxyphenyl or 4-phenoxyphenyl.
8. A compound according to claim 1, wherein Ar is 4-methoxyphenyl or 4-phenoxyphenyl and R3 and R4 are taken together to form (C3-C8)cycloalkanyl,
oxacyclohexanyl, thiocyclohexanyl, indanyl or a group of the formula
wherein R15 is (C1-C6)acyl, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C5-C9)heteroaryl(C1-C6)alkyl or (C1-C6)alkylsulfonyl.
9. A compound according to claim 1, wherein n is 2, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, R and R are taken together to form piperazinyl, (C1-C6)alkylpiperazinyl, (C6-C10)aryl piperazinyl or (C5- C9)heteroaryl(C1-C6)alkylpiperazinyl, and either R3 or R4 is not hydrogen or both R3 and R4 are not hydrogen.
10. A compound according to claim 1, wherein n is 2, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, R1 is hydrogen or (C1-C6)alkyl, R2 is 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl, and either R3 or R4 is not hydrogen or both R3 and R4 are not hydrogen.
11. A compound according to claim 1, wherein n is 1, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, R1 is hydrogen, R2 is 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl, and either R3 or R4 is not hydrogen or both R3 and R4 are not hydrogen.
12. A compound according to claim 2, wherein Ar is 4-methoxyphenyl, R1 is hydrogen or (C1-C6)alkyl and R2 is R5 (C2-C6)alkyl wherein R5 is morpholino, thiomorpholino, piperidino, pyrrolidino, (C1-C6)acylpiperazino, (C1-C6)alkylpiperazino, (C6- C10)arylpiperazino, (C5-C9)heteroarylpiperazino, (C6- C10)aryl(C1-C6)alkylpiperazino or (C5-C9)heteroaryl (C1-C6)alkylpiperazino and either R3 or R4 is not hydrogen or both R3 and R4 are not hydrogen.
13. A compound according to claim 1, wherein n is 1, Ar is 4-methoxyphenyl or 4-phenoxyphenyl, R1 is hydrogen, R2 is R5(C2-C6)alkyl wherein R5 is
morpholino, thiomorpholino, piperidino, pyrrolidino,
(C1-C6)acylpiperazino, (C1-C6)alkylpiperazino, (C6- C10)arylpiperazino, (C5-C9)heteroarylpiperazino, (C1- C10)aryl(C1-C6)alkylpiperazino or (C5-C9)heteroaryl (C1- C6)alkylpiperazino and either R3 or R4 is not hydrogen or both R3 and R4 are not hydrogen.
14. A compound according to claim 1, wherein said compound is selected from:
2-(R)-N-Hydroxy-2-[(4-methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino]-3-methylbutyramide;
2-(R)-2-[(2-Benzylcarbamoylethyl)(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyramide;
2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)(2-[(pyridin-3-ylmethyl)carbamoyl)ethyl)amino)-3-methylbutyramide;
2-(R)-N-Hydroxy-2-([4-methoxybenzenesulfonyl][2-(methylpyridin-3-ylmethylcarbamoyl)ethyl]amino)-3-methylbutyramide;
4-(3-[1-(R)-1-Hydroxycarbamoyl-2-methylpropyl)(4-methoxybenzenesulfonyl)amino]propionyl)piperazine-1- carboxylic acid, tert-butyl ester;
2-(R)-N-Hydroxy-2-[(4- methoxybenzenesulfonyl)(3-oxo-3-piperazin-1- ylpropyl)amino)-3-methylbutyramide hydrochloride;
2-(R)-2-[(Benzylcarbamoylmethyl)(4- methoxybenzenesulfonyl)amino]N-hydroxy-3-methylbutyramide;
2-(R)-N-Hydroxy-2-[(4-methoxybenzenesulfonyl]-[(2-morpholin-4-ylethylcarbamoyl)methyl]amino)-3-methylbutyramide;
2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)([(pyridin-3-ylmethyl)carbamoyl]methyl)amino)-3-methylbutyramide;
2-(R)-3,3,3-Trifluoro-N-hydroxy-2- [(methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino]propionamide;
2-(R)-N-Hydroxy-2-((4-phenoxybenzenesulfonyl)[2-(methylpyridin-4-ylmethylcarbamoyl)ether]amino)-3-methylbutyramide;
4-[4-Methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino]-1-methylpiperidene-4-carboxylic acid hydroxyamide;
2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)-[3-(4-methylpiperazin-1-yl)-3-oxopropyl]amino)-3-methylbutyramide;
2- (R)-2-[(2-Carboxyethyl)(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyramide;
[(2-Carboxyethyl)(3,4-dimethoxybenzenesulfonyl)amino]-N-hydroxy-acetamide;
2- (R)-2-[(2-Carbamoylethyl)(4-methoxybenzenesulfonyl)amino]-N-hydroxy-3-methylbutyramide;
2-(R),3-(R)-3,N-Dihydroxy-2-[(4-methoxybenzenesulfonyl)(3-oxo-3-piperidin-1-ylpropyl)amino]-butyramide;
2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)[3-(methylpyridin-3-ylmethylcarbamoyDpropyl]amino)-3-methylbutyramide;
2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)[2- (methylcarboxymethylcarbamoyl)ethyl]amino)-3- methylbutyramide;
2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)-[(1-methylpiperidin-4-ylcarbamoyl)methyl]amino)-3-methylbutyramide;
2- (R)-2-Clyclohexyl-N-hydroxy-2-((4-methoxybenzenesulfonyl)-[3-(4-methylpiperazin-1-yl)--¬oxopropyl]amino)-acetamide; and
2-(R)-N-Hydroxy-2- [(methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino]-4-(morpholin-4-yl)butyramide.
15. A pharmaceutical composition for (a) the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) or (b) the inhibition of matrix metalloproteinases or the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising an amount of a compound of claim 1 or a
pharmaceutically acceptable salt thereof, effective in such treatments and a pharmaceutically acceptable carrier.
16. A method for the inhibition of (a) matrix metalloproteinases or (b) the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
17. A method for treating a condition selected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease,
epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity,
AIDS, sepsis, septic shock and other diseases involving the production of tumor necrosis factor (TNF) in a mammal, including a human, comprising administering to said mammal an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, effective in treating such a condition.
18. A method of preparing a compound of the formula
n is 1 to 6;
X is hydroxy, (C1-C6)alkoxy or NR1R2 wherein R1 and R2 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C5-C9)heteroarylpiperidyl, (C6-C10)aryl(C1-C6)alkylpiperidyl, (C5-C9)heteroaryl(C1-C6)alkylpiperidyl, (C1-C6)acylpiperidyl, (C8-C10)aryl, (C5-C9)heteroaryl, (C6-C10) aryl (C1-C6) alkyl, (C5-C9)heteroaryl(C1-C6)alkyl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C8-C10)aryl(C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, R5(C2-C6)alkyl, (C1-C6)alkyl(CHR5)(C1-C6)alkyl wherein R5 is hydroxy, (C1-C6)acyloxy, (C1-C6)alkoxy, piperazino, (C1-C6)acylamino, (C1-C6)alkylthio, (C6-C10) arylthio, (C1-C6)alkylsulfinyl, (C6-C10)arylsulfinyl, (C1- C6)alkylsulfoxyl, (C6-C10)arylsulfoxyl, amino, (C1- C6)alkylamino, ((C1-C6)alkyl)2amino, (C1- C6)acylpiperazino, (C1-C6)alkylpiperazino, (C6- C10)aryl(C1-C6)alkylpiperazino, (C5-C9)heteroaryl(C1- C6)alkylpiperazino, morpholino, thiomorpholino,
piperidino or pyrrolidino; R6 (C1-C6)alkyl, (C1-C5)alkyl(CHR6)(C1-C6)alkyl wherein R6 is piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C6-C10)aryl(C1-C6)alkylpiperidyl, (C5-C9)heteroarylpiperidyl or (C5-C9)heteroaryl(C1-C6)alkylpiperidyl; and CH(R7)COR8 wherein R7 is
hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl, (C5-C9)heteroaryl(C1-C6)alkyl, (C1-C6)alkylthio(C1-C6)alkyl, (C6-C10)arylthio(C1-C6)alkyl, (C1- C6)alkylsulfinyKC1-C6)alkyl, (C8-C10)arylsulfinyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C6-C10)arylsulfonyl(C1-C6)alkyl, hydroxy (C1-C6)alkyl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkylamino)2(C1-C6)alkyl, R9R10NCO (C1-C6)alkyl or R9OCO(C1-C6)alkyl wherein R9 and R10 are each
independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl and (C5-C9)heteroaryl(C1-C6)alkyl; and R8 is R11O or
R11R12N wherein R11 and R12 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl and (C5-C9)heteroaryl(C1-C6)alkyl;
or R1 and R2, or R9 and R10, or R11 and R12 may be taken together to form an azetidinyl,
pyrrolidinyl, morpholinyl, thiomorpholinyl, indolinyl, isoindolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, (C1-C6)acylpiperazinyl, (C1- C6)alkylpiperazinyl, (C6-C10)arylpiperazinyl, (C5- C9)heteroarylpiperazinyl or a bridged diazabicycloalkyl ring selected from the group consisting of
wherein r is 1, 2 or 3;
m is 1 or 2;
p is 0 or 1; and
Q is hydrogen, (C1-C3)alkyl or (C1-C6)acyl; R3 and R4 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, trifluoromethyl, trifluoromethyl (C1-C6) alkyl, (C1-C6)alkyl (difluoromethylene), (C1- C3)alkyl (difluoromethylene) (C1-C3)alkyl, (C6-C10)aryl (C5-C9)heteroaryl, (C6-C10)aryl(C1-C6)alkyl, (C5-Cg)heteroaryl(C1-C6)alkyl, (C6-C10)aryl(C6-C10)aryl, (C6-C10)aryl(C6-C10)aryl(C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl,
hydroxy(C1-C6)alkyl, (C1-C6)acyloxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, piperazinyl (C1-C6)alkyl, (C1-C6)acylamino(C1-C6)alkyl, piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)aryl(C1-C6)alkoxy(C1-C6)alkyl, C5-C8)heteroaryl(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkylthio(C1-C6)alkyl, (C6-C10)arylthio(C1- C6)alkyl, (C1-C6)alkylsulfinyl(C1-C6)alkyl, (C6-C10)arylsulfinyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C6-C10)arylsulfonyl(C1-C6)alkyl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkylamino)2(C1-C6)alkyl, R13CO(C1-C6)alkyl wherein
R13 is R20O or R20R21N wherein R20 and R21 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C8-C10)aryl(C1-C6)alkyl or
(C5-C9)heteroaryl(C1-C6)alkyl; or R14(C1-C6)alkyl wherein R14 is (C1-C6)acylpiperazino, (C6- C10)arylpiperazino, (C5-C9)heteroarylpiperazino, (C1-C6)alkylpiperazino, (C6-C10)aryl(C1-C6)alkylpiperazino,
(C5-C9) heteroaryl (C1-C6)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C1-C6)alkylpiperidyl, (C6-C10)arylpiperidyl, (C5-C9)heteroarylpiperidyl, (C6-C10)aryl(C1-C6)alkylpiperidyl, (C5-C9)heteroaryl(C1-C6)alkylpiperidyl or (C1-C6)acylpiperidyl;
or R3 and R4, or R20 and R21 may be taken together to form a (C3-C6)cycloalkyl, oxacyclohexyl, thiocyclohexyl, indanyl or tetralinyl ring or a group of the formula
with the proviso that when either R1 or R2 is
CH(R7)COR8 wherein R7 and R8 are as defined above, the other of R1 or R2 is hydrogen, (C1-C6)alkyl or benzyl; comprising reacting a compound of the formula
wherein n, X, R3, R4 and Ar are as defined above with
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenztriazole and hydroxylamine.
Priority Applications (15)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/894,873US5863949A (en) | 1995-03-08 | 1995-03-07 | Arylsulfonylamino hydroxamic acid derivatives |
| DK96907134TDK0813520T3 (en) | 1995-03-08 | 1996-03-07 | Arylsulfonylamino hydroxamic acid derivatives |
| AT96907134TATE211131T1 (en) | 1995-03-08 | 1996-03-07 | ARYLSULFONYLAMINOHYDROXAMIC ACID DERIVATIVES |
| BR9607362ABR9607362A (en) | 1995-03-08 | 1996-03-07 | Aryl sulfonyl amino hydroxamic acid derivatives |
| NZ303860ANZ303860A (en) | 1995-03-08 | 1996-03-07 | Arylsulfonylamino hyroxamic acid derivatives and pharmaceutical compositions thereof |
| DE69618179TDE69618179T2 (en) | 1995-03-08 | 1996-03-07 | ARYLSULFONYLAMINOHYDROXAMSÄUREDERIVATE |
| RU97116727ARU2145597C1 (en) | 1995-03-08 | 1996-03-07 | Derivatives of arylsulfonylaminohydroxamic acid, method of their synthesis, pharmaceutical composition, method of inhibition of matrix metalloproteinases and method of patient treatment |
| PL96322131APL184158B1 (en) | 1995-03-08 | 1996-03-07 | Derivatives of arylosulphonylamino hydroxamic acid |
| JP52691896AJP3753737B2 (en) | 1995-03-08 | 1996-03-07 | Arylsulfonylaminohydroxamic acid derivatives |
| CA002214720ACA2214720C (en) | 1995-03-08 | 1996-03-07 | Arylsulfonylamino hydroxamic acid derivatives |
| EP96907134AEP0813520B1 (en) | 1995-03-08 | 1996-03-07 | Arylsulfonylamino hydroxamic acid derivatives |
| FI973613AFI973613L (en) | 1995-03-08 | 1996-03-07 | Arylsulfonylaminohydroxamic acid derivatives |
| MX9706850AMX9706850A (en) | 1995-03-08 | 1996-03-07 | Arylsulfonylamino hydroxamic acid derivatives. |
| AU50293/96AAU707510B2 (en) | 1995-03-08 | 1996-03-07 | Arylsulfonylamino hydroxamic acid derivatives |
| NO19974103ANO313752B1 (en) | 1995-03-08 | 1997-09-05 | Arylsulfonylaminohydroxamic acid derivatives, their use and pharmaceutical composition |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US40104995A | 1995-03-08 | 1995-03-08 | |
| US08/401,049 | 1995-03-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996027583A1true WO1996027583A1 (en) | 1996-09-12 |
Family
ID=23586059
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1996/002679WO1996027583A1 (en) | 1995-03-08 | 1996-03-07 | Arylsulfonylamino hydroxamic acid derivatives |
Country Status (31)
| Country | Link |
|---|---|
| US (1) | US5863949A (en) |
| EP (1) | EP0813520B1 (en) |
| JP (1) | JP3753737B2 (en) |
| KR (1) | KR100269046B1 (en) |
| CN (2) | CN1122662C (en) |
| AR (1) | AR003935A1 (en) |
| AT (1) | ATE211131T1 (en) |
| AU (1) | AU707510B2 (en) |
| BR (1) | BR9607362A (en) |
| CA (1) | CA2214720C (en) |
| CO (1) | CO4700432A1 (en) |
| CZ (1) | CZ291106B6 (en) |
| DE (1) | DE69618179T2 (en) |
| DK (1) | DK0813520T3 (en) |
| ES (1) | ES2169794T3 (en) |
| FI (1) | FI973613L (en) |
| HK (1) | HK1041254A1 (en) |
| HU (1) | HUP9800462A3 (en) |
| IL (1) | IL117343A (en) |
| MX (1) | MX9706850A (en) |
| MY (1) | MY113586A (en) |
| NO (1) | NO313752B1 (en) |
| NZ (1) | NZ303860A (en) |
| PE (1) | PE28797A1 (en) |
| PL (1) | PL184158B1 (en) |
| PT (1) | PT813520E (en) |
| RU (1) | RU2145597C1 (en) |
| TR (1) | TR199700913T1 (en) |
| TW (1) | TW346488B (en) |
| WO (1) | WO1996027583A1 (en) |
| ZA (1) | ZA961876B (en) |
Cited By (340)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998007697A1 (en)* | 1996-08-23 | 1998-02-26 | Pfizer Inc. | Arylsulfonylamino hydroxamic acid derivatives |
| WO1998015525A1 (en)* | 1996-10-07 | 1998-04-16 | Sumitomo Pharmaceuticals Co., Ltd. | Hydroxamic acids |
| WO1998016503A3 (en)* | 1996-10-16 | 1998-05-28 | American Cyanamid Co | The preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase and tace inhibitors |
| US5770624A (en)* | 1995-12-15 | 1998-06-23 | Novartis Corp. | Certain alpha-substituted arylsulfonamido acetohydroxamic acids |
| WO1998031664A1 (en)* | 1997-01-17 | 1998-07-23 | Pharmacia & Upjohn Company | Bis-sulfonomides hydroxamic acids as mmp inhibitors |
| WO1998033768A1 (en)* | 1997-02-03 | 1998-08-06 | Pfizer Products Inc. | Arylsulfonylamino hydroxamic acid derivatives |
| US5804593A (en)* | 1996-10-22 | 1998-09-08 | Pharmacia & Upjohn Company | α-Amino sulfonyl hydroxamic acids as matrix metalloproteinase inhibitors |
| US5817822A (en)* | 1994-06-24 | 1998-10-06 | Novartis Corporation | Certain alpha-azacycloalkyl substituted arylsulfonamido acetohydroxamic acids |
| WO1998043963A1 (en)* | 1997-04-01 | 1998-10-08 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
| EP0877018A1 (en)* | 1997-05-09 | 1998-11-11 | Hoechst Aktiengesellschaft | Sulfonylaminocarboxylic acids |
| EP0877019A1 (en)* | 1997-05-09 | 1998-11-11 | Hoechst Aktiengesellschaft | Substituted diaminocarboxylic acid |
| WO1998050348A1 (en)* | 1997-05-09 | 1998-11-12 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
| EP0895988A1 (en)* | 1997-08-08 | 1999-02-10 | Pfizer Products Inc. | Arylsulfonylamino hydroxamic acid derivatives |
| WO1999007675A1 (en)* | 1997-08-08 | 1999-02-18 | Pfizer Products Inc. | Aryloxyarylsulfonylamino hydroxamic acid derivatives |
| US5929097A (en)* | 1996-10-16 | 1999-07-27 | American Cyanamid Company | Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase and tace inhibitors |
| US5962471A (en)* | 1997-05-13 | 1999-10-05 | Hoechst Aktiengesellschaft | Substituted 6- and 7-aminotetrahydroisoquinolinecarboxylic acids |
| US5962481A (en)* | 1996-10-16 | 1999-10-05 | American Cyanamid Company | Preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors |
| EP0949245A1 (en)* | 1998-04-10 | 1999-10-13 | Pfizer Products Inc. | Process for alkylating hindered sulfonamides |
| WO1999052910A1 (en)* | 1998-04-10 | 1999-10-21 | Pfizer Products Inc. | Bicyclic hydroxamic acid derivatives |
| EP0952148A1 (en)* | 1998-04-10 | 1999-10-27 | Pfizer Products Inc. | Cyclobutyl-aryloxyarylsulfonylamino hydroxamic acid derivatives |
| US5977408A (en)* | 1996-10-16 | 1999-11-02 | American Cyanamid Company | Preparation and use of β-sulfonamido hydroxamic acids as matrix metalloproteinase and TACE inhibitors |
| US5985900A (en)* | 1997-04-01 | 1999-11-16 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
| US5998412A (en)* | 1997-01-23 | 1999-12-07 | Syntex (U.S.A.) Inc. | Sulfamide-metalloprotease inhibitors |
| US6008243A (en)* | 1996-10-24 | 1999-12-28 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them, and their use |
| US6022873A (en)* | 1996-10-19 | 2000-02-08 | British Biotech Pharmaceuticals Limited | Metalloproteinase inhibitors |
| EP0977745A4 (en)* | 1997-03-04 | 2000-05-31 | Monsanto Co | Thioaryl sulfonamide hydroxamic acid compounds |
| US6107337A (en)* | 1998-08-06 | 2000-08-22 | Pfizer Inc. | Arylsulfonylamino hydroxamic acid derivatives |
| US6118016A (en)* | 1998-04-10 | 2000-09-12 | Pfizer Inc. | Process for preparing phenoxyphenylsulfonyl halides |
| US6130220A (en)* | 1997-10-16 | 2000-10-10 | Syntex (Usa) Inc. | Sulfamide-metalloprotease inhibitors |
| WO2000063165A1 (en)* | 1999-04-19 | 2000-10-26 | Fujisawa Pharmaceutical Co., Ltd. | Mmp inhibitor |
| US6153757A (en)* | 1995-12-08 | 2000-11-28 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors and intermediates useful for their preparation |
| US6174915B1 (en) | 1997-03-25 | 2001-01-16 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
| US6201130B1 (en) | 1998-11-06 | 2001-03-13 | Aventis Pharma Duetschland Gmbh | N-arylsulfonylamino acid omega-amides |
| US6200996B1 (en) | 1999-01-27 | 2001-03-13 | American Cyanamid Company | Heteroaryl acetylenic sulfonamide and phosphinic acid amide hydroxamic acid tace inhibitors |
| EP1088550A1 (en)* | 1999-10-01 | 2001-04-04 | Pfizer Products Inc. | alpha-sulfonylamino hydroxamic acid inhibitors of matrix metallo-proteinases for the treatment of peripheral or central nervous system disorders |
| US6225311B1 (en) | 1999-01-27 | 2001-05-01 | American Cyanamid Company | Acetylenic α-amino acid-based sulfonamide hydroxamic acid tace inhibitors |
| US6228869B1 (en) | 1996-10-16 | 2001-05-08 | American Cyanamid Company | Ortho-sulfonamido bicyclic hydroxamic acids as matrix metalloproteinase and TACE inhibitors |
| US6235727B1 (en) | 1998-07-16 | 2001-05-22 | Aventis Pharma Deutschland Gmbh | Sulfonylaminophosphinic and sulfonylaminophosphinic acid derivatives, methods for their preparation and use |
| US6277885B1 (en) | 1999-01-27 | 2001-08-21 | American Cyanamid Company | Acetylenic aryl sulfonamide and phosphinic acid amide hydroxamic acid TACE inhibitors |
| US6288246B1 (en) | 1998-04-10 | 2001-09-11 | Pfizer Inc | Process for preparing hydroxamic acids |
| US6313123B1 (en) | 1999-01-27 | 2001-11-06 | American Cyanamid Company | Acetylenic sulfonamide thiol tace inhibitors |
| US6326516B1 (en) | 1999-01-27 | 2001-12-04 | American Cyanamid Company | Acetylenic β-sulfonamido and phosphinic acid amide hydroxamic acid TACE inhibitors |
| US6340691B1 (en) | 1999-01-27 | 2002-01-22 | American Cyanamid Company | Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase and tace inhibitors |
| US6358980B1 (en) | 1999-01-27 | 2002-03-19 | American Cyanamid Company | Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase/tace inhibitors |
| US6376506B1 (en) | 1997-01-23 | 2002-04-23 | Syntex (U.S.A.) Llc | Sulfamide-metalloprotease inhibitors |
| US6458822B2 (en) | 2000-03-13 | 2002-10-01 | Pfizer Inc. | 2-oxo-imidazolidine-4-carboxylic acid hydroxamide compounds that inhibit matrix metalloproteinases |
| US6465508B1 (en) | 2000-02-25 | 2002-10-15 | Wyeth | Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase inhibitors |
| US6506936B1 (en) | 1999-02-25 | 2003-01-14 | Fibrogen, Inc. | N-substituted arylsulfonylamino hydroxamic acids useful as inhibitors of c-proteinase and for treating or preventing disorders related to unregulated collagen production |
| US6548524B2 (en) | 1996-10-16 | 2003-04-15 | American Cyanamid Company | Preparation and use of ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and TACE inhibitors |
| WO2003040098A1 (en)* | 2001-11-07 | 2003-05-15 | Astrazeneca Ab | Novel metalloproteinase inhibitors |
| US6716853B2 (en) | 2002-03-02 | 2004-04-06 | Aventis Pharma Deutschland Gmbh | Cyclic N-substituted alpha-imino carboxylic acids for selective inhibition of collogenase |
| EP1415984A1 (en)* | 1997-08-08 | 2004-05-06 | Pfizer Products Inc. | Aryloxyarylsulfonylamino hydroxamic acid derivatives |
| US6753337B2 (en) | 1999-01-27 | 2004-06-22 | Wyeth Holdings Corporation | Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase/tace inhibitors |
| US6762178B2 (en) | 1999-01-27 | 2004-07-13 | Wyeth Holdings Corporation | Acetylenic aryl sulfonamide and phosphinic acid amide hydroxamic acid TACE inhibitors |
| US6833456B2 (en) | 2002-03-01 | 2004-12-21 | Agouron Pharmaceuticals, Inc. | Indolyl-urea derivatives of thienopyridines useful as antiangiogenic agents, and methods for their use |
| WO2004113279A1 (en)* | 2003-06-20 | 2004-12-29 | Glaxo Group Limited | Inhibitors of matrix metalloproteinase |
| US6858598B1 (en) | 1998-12-23 | 2005-02-22 | G. D. Searle & Co. | Method of using a matrix metalloproteinase inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia |
| WO2005016967A2 (en) | 2003-08-13 | 2005-02-24 | Pfizer Products Inc. | Modified human igf-1r antibodies |
| WO2005023759A2 (en) | 2003-09-03 | 2005-03-17 | Array Biopharma Inc. | Heterocyclic inhibitors of mek and methods of use thereof |
| US6869962B2 (en) | 2002-06-14 | 2005-03-22 | Agouron Pharmaceuticals, Inc. | Benzofused heterozryl amide derivatives of thienopyridines useful as therapeutic agents, pharmaceutical compositions including the same, and methods for their use |
| WO2005051300A2 (en) | 2003-11-19 | 2005-06-09 | Array Biopharma Inc. | Bicyclic inhibitors of mek and methods of use thereof |
| US6946473B2 (en) | 1999-01-27 | 2005-09-20 | Wyeth Holdings Corporation | Preparation and use of acetylenic ortho-sulfonamido and phosphinic acid amido bicyclic heteroaryl hydroxamic acids as TACE inhibitors |
| US6995171B2 (en) | 2001-06-21 | 2006-02-07 | Agouron Pharmaceuticals, Inc. | Bicyclic pyrimidine and pyrimidine derivatives useful as anticancer agents |
| US7022846B2 (en) | 2002-06-10 | 2006-04-04 | Agouron Pharmaceuticals, Inc. | Metabolites of prinomastat and their synthesis |
| US7037498B2 (en) | 2001-01-05 | 2006-05-02 | Abgenix, Inc. | Antibodies to insulin-like growth factor I receptor |
| US7053107B2 (en) | 2002-12-19 | 2006-05-30 | Agouron Pharmaceuticals, Inc. | Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use |
| RU2284185C2 (en)* | 2002-01-08 | 2006-09-27 | Маттиас Рат | Composition inhibiting matrix metalloproteinases for treatment of neoplasm diseases |
| WO2007035744A1 (en) | 2005-09-20 | 2007-03-29 | Osi Pharmaceuticals, Inc. | Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors |
| US7199155B2 (en) | 2002-12-23 | 2007-04-03 | Wyeth Holdings Corporation | Acetylenic aryl sulfonate hydroxamic acid TACE and matrix metalloproteinase inhibitors |
| WO2007044084A2 (en) | 2005-05-18 | 2007-04-19 | Array Biopharma Inc. | Heterocyclic inhibitors of mek and methods of use thereof |
| US7208500B2 (en) | 2003-08-29 | 2007-04-24 | Agouron Pharmaceuticals, Inc. | Thienopyridine-phenylacetamides and their derivatives useful as new anti-angiogenic agents |
| WO2007076245A2 (en) | 2005-12-21 | 2007-07-05 | Array Biopharma Inc. | Novel hydrogen sulfate salt |
| US7282496B2 (en) | 2001-11-01 | 2007-10-16 | Wyeth Holdings Corporation | Allenic aryl sulfonamide hydroxamic acids as matrix metalloproteinase and TACE inhibitors |
| US7288251B2 (en) | 2001-11-09 | 2007-10-30 | Abgenix, Inc. | Antibodies to CD40 |
| US7326414B2 (en) | 2003-09-10 | 2008-02-05 | Warner-Lambert Company Llc | Antibodies to M-CSF |
| US7354940B2 (en) | 2002-08-27 | 2008-04-08 | Astrazeneca Ab | 2,5-dioxoimidazolidin-4-yl acetamines and analogues as inhibitors of metalloproteinase mmp12 |
| US7368465B2 (en) | 2001-03-15 | 2008-05-06 | Astrazeneca Ab | Metalloproteinase inhibitors |
| WO2008075196A1 (en) | 2006-12-15 | 2008-06-26 | Pfizer Products Inc. | Benzimidazole derivatives |
| US7399770B2 (en) | 2004-01-31 | 2008-07-15 | Sanofi-Aventis Deutschland Gmbh | Thieno-imino acid derivatives for use as matrix metalloproteinase inhibitors |
| US7429667B2 (en) | 2005-01-20 | 2008-09-30 | Ardea Biosciences, Inc. | Phenylamino isothiazole carboxamidines as MEK inhibitors |
| WO2008129380A1 (en) | 2007-04-18 | 2008-10-30 | Pfizer Products Inc. | Sulfonyl amide derivatives for the treatment of abnormal cell growth |
| WO2009018238A1 (en) | 2007-07-30 | 2009-02-05 | Ardea Biosciences, Inc. | Combinations of mek inhibitors and raf kinase inhibitors and uses thereof |
| US7498420B2 (en) | 2003-08-04 | 2009-03-03 | Amgen Fremont Inc. | Antibodies to c-Met |
| WO2009082687A1 (en) | 2007-12-21 | 2009-07-02 | Genentech, Inc. | Azaindolizines and methods of use |
| US7579487B2 (en) | 2004-05-11 | 2009-08-25 | Merck & Co., Inc. | Process for making N-sulfonated-amino acid derivatives |
| WO2009114870A2 (en) | 2008-03-14 | 2009-09-17 | Intellikine, Inc. | Kinase inhibitors and methods of use |
| US7618626B2 (en) | 2004-07-16 | 2009-11-17 | Pfizer Inc | Combination treatment for non-hematologic malignancies |
| EP2130537A1 (en) | 2002-03-13 | 2009-12-09 | Array Biopharma, Inc. | N3 alkylated benzimidazole derivatives as mek inhibitors |
| US7648992B2 (en) | 2004-07-05 | 2010-01-19 | Astrazeneca Ab | Hydantoin derivatives for the treatment of obstructive airway diseases |
| US7655664B2 (en) | 2004-12-17 | 2010-02-02 | Astrazeneca Ab | Hydantoin derivatives as metalloproteinase inhibitors |
| US7700604B2 (en) | 2004-12-17 | 2010-04-20 | Astrazeneca Ab | Hydantoin derivatives as metalloproteinase inhibitors |
| WO2010045495A2 (en) | 2008-10-16 | 2010-04-22 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Fully human antibodies to high molecular weight-melanoma associated antigen and uses thereof |
| WO2010051043A1 (en) | 2008-11-03 | 2010-05-06 | Intellikine, Inc. | Benzoxazole kinase inhibitors and methods of use |
| US7759518B2 (en) | 2005-07-21 | 2010-07-20 | Ardea Biosciences | Derivatives of N-(arylamino) sulfonamides as inhibitors of MEK |
| US7772270B2 (en) | 2003-01-03 | 2010-08-10 | Sanofi-Aventis Deutschland Gmbh | Imino acid derivatives as inhibitors of matrix metalloproteinases |
| WO2010091150A1 (en) | 2009-02-05 | 2010-08-12 | Immunogen, Inc. | Novel benzodiazepine derivatives |
| WO2010090764A1 (en) | 2009-02-09 | 2010-08-12 | Supergen, Inc. | Pyrrolopyrimidinyl axl kinase inhibitors |
| WO2010099138A2 (en) | 2009-02-27 | 2010-09-02 | Osi Pharmaceuticals, Inc. | Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation |
| WO2010099139A2 (en) | 2009-02-25 | 2010-09-02 | Osi Pharmaceuticals, Inc. | Combination anti-cancer therapy |
| WO2010099364A2 (en) | 2009-02-27 | 2010-09-02 | Osi Pharmaceuticals, Inc. | Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation |
| WO2010099363A1 (en) | 2009-02-27 | 2010-09-02 | Osi Pharmaceuticals, Inc. | Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation |
| WO2010099137A2 (en) | 2009-02-26 | 2010-09-02 | Osi Pharmaceuticals, Inc. | In situ methods for monitoring the emt status of tumor cells in vivo |
| WO2010098866A1 (en) | 2009-02-27 | 2010-09-02 | Supergen, Inc. | Cyclopentathiophene/cyclohexathiophene dna methyltransferase inhibitors |
| WO2010108652A1 (en) | 2009-03-27 | 2010-09-30 | Ardea Biosciences Inc. | Dihydropyridin sulfonamides and dihydropyridin sulfamides as mek inhibitors |
| US7820664B2 (en) | 2007-01-19 | 2010-10-26 | Bayer Schering Pharma Ag | Inhibitors of MEK |
| WO2010129816A2 (en) | 2009-05-07 | 2010-11-11 | Intellikine, Inc. | Heterocyclic compounds and uses thereof |
| US7842836B2 (en) | 2006-04-11 | 2010-11-30 | Ardea Biosciences | N-aryl-N'alkyl sulfamides as MEK inhibitors |
| US7858643B2 (en) | 2004-08-26 | 2010-12-28 | Agouron Pharmaceuticals, Inc. | Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors |
| WO2011014726A1 (en) | 2009-07-31 | 2011-02-03 | Osi Pharmaceuticals, Inc. | Mtor inhibitor and angiogenesis inhibitor combination therapy |
| WO2011022439A1 (en) | 2009-08-17 | 2011-02-24 | Intellikine, Inc. | Heterocyclic compounds and uses thereof |
| US7897624B2 (en) | 2006-04-18 | 2011-03-01 | Ardea Biosciences | Pyridone sulfonamides and pyridone sulfamides as MEK inhibitors |
| EP2292233A2 (en) | 1999-11-11 | 2011-03-09 | OSI Pharmaceuticals, Inc. | Pharmaceutical uses of N-(3-Ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine |
| WO2011027249A2 (en) | 2009-09-01 | 2011-03-10 | Pfizer Inc. | Benzimidazole derivatives |
| WO2011049625A1 (en) | 2009-10-20 | 2011-04-28 | Mansour Samadpour | Method for aflatoxin screening of products |
| EP2322550A1 (en) | 2004-12-22 | 2011-05-18 | Amgen, Inc | Compositions comprising anti-IGF-1R Antibodies and Methods for obtaining said Antibodies |
| US7989620B2 (en) | 2004-07-05 | 2011-08-02 | Astrazeneca Ab | Hydantoin derivatives for the treatment of obstructive airway diseases |
| WO2011098971A1 (en) | 2010-02-12 | 2011-08-18 | Pfizer Inc. | Salts and polymorphs of 8-fluoro-2-{4-[(methylamino}methyl]phenyl}-1,3,4,5-tetrahydro-6h-azepino[5,4,3-cd]indol-6-one |
| WO2011100403A1 (en) | 2010-02-10 | 2011-08-18 | Immunogen, Inc | Cd20 antibodies and uses thereof |
| WO2011109584A2 (en) | 2010-03-03 | 2011-09-09 | OSI Pharmaceuticals, LLC | Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors |
| WO2011109572A2 (en) | 2010-03-03 | 2011-09-09 | OSI Pharmaceuticals, LLC | Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors |
| WO2011145035A1 (en) | 2010-05-17 | 2011-11-24 | Indian Incozen Therapeutics Pvt. Ltd. | Novel 3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued -3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of protein kinases |
| WO2011146882A1 (en) | 2010-05-21 | 2011-11-24 | Intellikine, Inc. | Chemical compounds, compositions and methods for kinase modulation |
| WO2012052948A1 (en) | 2010-10-20 | 2012-04-26 | Pfizer Inc. | Pyridine- 2- derivatives as smoothened receptor modulators |
| WO2012064973A2 (en) | 2010-11-10 | 2012-05-18 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| US8183251B2 (en) | 2006-11-29 | 2012-05-22 | Astrazeneca Ab | Hydantoin compounds and pharmaceutical compositions thereof |
| EP2476667A2 (en) | 2003-02-26 | 2012-07-18 | Sugen, Inc. | Aminoheteroaryl compounds as protein kinase inhibitors |
| WO2012097000A1 (en) | 2011-01-10 | 2012-07-19 | Pingda Ren | Processes for preparing isoquinolinones and solid forms of isoquinolinones |
| WO2012106556A2 (en) | 2011-02-02 | 2012-08-09 | Amgen Inc. | Methods and compositons relating to inhibition of igf-1r |
| WO2012112708A1 (en) | 2011-02-15 | 2012-08-23 | Immunogen, Inc. | Cytotoxic benzodiazepine derivatives and methods of preparation |
| WO2012116040A1 (en) | 2011-02-22 | 2012-08-30 | OSI Pharmaceuticals, LLC | Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors in hepatocellular carcinoma |
| WO2012116237A2 (en) | 2011-02-23 | 2012-08-30 | Intellikine, Llc | Heterocyclic compounds and uses thereof |
| WO2012142164A1 (en) | 2011-04-12 | 2012-10-18 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Human monoclonal antibodies that bind insulin-like growth factor (igf) i and ii |
| WO2012145183A2 (en) | 2011-04-19 | 2012-10-26 | Pfizer Inc. | Combinations of anti-4-1bb antibodies and adcc-inducing antibodies for the treatment of cancer |
| WO2012149014A1 (en) | 2011-04-25 | 2012-11-01 | OSI Pharmaceuticals, LLC | Use of emt gene signatures in cancer drug discovery, diagnostics, and treatment |
| WO2012151525A1 (en) | 2011-05-04 | 2012-11-08 | Rhizen Pharmaceuticals Sa | Novel compounds as modulators of protein kinases |
| WO2013012915A1 (en) | 2011-07-19 | 2013-01-24 | Infinity Pharmaceuticals Inc. | Heterocyclic compounds and uses thereof |
| WO2013012918A1 (en) | 2011-07-19 | 2013-01-24 | Infinity Pharmaceuticals Inc. | Heterocyclic compounds and uses thereof |
| WO2013032591A1 (en) | 2011-08-29 | 2013-03-07 | Infinity Pharmaceuticals Inc. | Heterocyclic compounds and uses thereof |
| WO2013042006A1 (en) | 2011-09-22 | 2013-03-28 | Pfizer Inc. | Pyrrolopyrimidine and purine derivatives |
| WO2013049332A1 (en) | 2011-09-29 | 2013-04-04 | Infinity Pharmaceuticals, Inc. | Inhibitors of monoacylglycerol lipase and methods of their use |
| WO2013050725A1 (en) | 2011-10-04 | 2013-04-11 | King's College London | Ige anti -hmw-maa antibody |
| WO2013068902A1 (en) | 2011-11-08 | 2013-05-16 | Pfizer Inc. | Methods of treating inflammatory disorders using anti-m-csf antibodies |
| US8455497B2 (en) | 1999-06-11 | 2013-06-04 | Vertex Pharmaceuticals Incorporated | Inhibitors of aspartyl protease |
| WO2013126617A1 (en) | 2012-02-22 | 2013-08-29 | The Regents Of The University Of Colorado, A Body Corporate | Bouvardin derivatives and therapeutic uses thereof |
| US8530463B2 (en) | 2007-05-07 | 2013-09-10 | Hale Biopharma Ventures Llc | Multimodal particulate formulations |
| WO2013144737A2 (en) | 2012-03-30 | 2013-10-03 | Rhizen Pharmaceuticals Sa | Novel 3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued -3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of c-met protein kinases |
| WO2013152252A1 (en) | 2012-04-06 | 2013-10-10 | OSI Pharmaceuticals, LLC | Combination anti-cancer therapy |
| WO2013154878A1 (en) | 2012-04-10 | 2013-10-17 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| WO2013185115A1 (en) | 2012-06-08 | 2013-12-12 | Sutro Biopharma, Inc. | Antibodies comprising site-specific non-natural amino acid residues, methods of their preparation and methods of their use |
| EP2690101A1 (en) | 2007-12-19 | 2014-01-29 | Genentech, Inc. | 5-Anilinoimidazopyridines and Methods of Use |
| WO2014031566A1 (en) | 2012-08-22 | 2014-02-27 | Immunogen, Inc. | Cytotoxic benzodiazepine derivatives |
| WO2014036492A1 (en) | 2012-08-31 | 2014-03-06 | Sutro Biopharma, Inc. | Modified amino acids comprising an azido group |
| WO2014071109A1 (en) | 2012-11-01 | 2014-05-08 | Infinity Pharmaceuticals, Inc. | Treatment of cancers using pi3 kinase isoform modulators |
| WO2014134483A2 (en) | 2013-02-28 | 2014-09-04 | Immunogen, Inc. | Conjugates comprising cell-binding agents and cytotoxic agents |
| WO2014134486A2 (en) | 2013-02-28 | 2014-09-04 | Immunogen, Inc. | Conjugates comprising cell-binding agents and cytotoxic agents |
| WO2014143659A1 (en) | 2013-03-15 | 2014-09-18 | Araxes Pharma Llc | Irreversible covalent inhibitors of the gtpase k-ras g12c |
| WO2014151386A1 (en) | 2013-03-15 | 2014-09-25 | Infinity Pharmaceuticals, Inc. | Salts and solid forms of isoquinolinones and composition comprising and methods of using the same |
| WO2014151147A1 (en) | 2013-03-15 | 2014-09-25 | Intellikine, Llc | Combination of kinase inhibitors and uses thereof |
| WO2014152588A1 (en) | 2013-03-15 | 2014-09-25 | Araxes Pharma Llc | Covalent inhibitors of kras g12c |
| US8895546B2 (en) | 2009-03-27 | 2014-11-25 | Hale Biopharma Ventures, Llc | Administration of benzodiazepine compositions |
| WO2014194254A1 (en) | 2013-05-30 | 2014-12-04 | Infinity Pharmaceuticals, Inc. | Treatment of cancers using pi3 kinase isoform modulators |
| WO2014194030A2 (en) | 2013-05-31 | 2014-12-04 | Immunogen, Inc. | Conjugates comprising cell-binding agents and cytotoxic agents |
| WO2015006555A2 (en) | 2013-07-10 | 2015-01-15 | Sutro Biopharma, Inc. | Antibodies comprising multiple site-specific non-natural amino acid residues, methods of their preparation and methods of their use |
| WO2015051244A1 (en) | 2013-10-04 | 2015-04-09 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| WO2015051241A1 (en) | 2013-10-04 | 2015-04-09 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| WO2015051341A1 (en) | 2013-10-03 | 2015-04-09 | Araxes Pharma Llc | Inhibitors of erk and methods of use |
| WO2015054572A1 (en) | 2013-10-10 | 2015-04-16 | Araxes Pharma Llc | Inhibitors of kras g12c |
| WO2015054658A1 (en) | 2013-10-11 | 2015-04-16 | Sutro Biopharma, Inc. | Modified amino acids comprising tetrazine functional groups, methods of preparation, and methods of their use |
| WO2015061204A1 (en) | 2013-10-21 | 2015-04-30 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| US9034861B2 (en) | 2009-10-13 | 2015-05-19 | Allomek Therapeutics Llc | MEK inhibitors useful in the treatment of diseases |
| WO2015075598A1 (en) | 2013-11-21 | 2015-05-28 | Pfizer Inc. | 2,6-substituted purine derivatives and their use in the treatment of proliferative disorders |
| EP2918589A1 (en) | 2009-07-15 | 2015-09-16 | Intellikine, LLC | Adenine derivative as pi3k inhibitor |
| WO2015155624A1 (en) | 2014-04-10 | 2015-10-15 | Pfizer Inc. | Dihydropyrrolopyrimidine derivatives |
| WO2015168079A1 (en) | 2014-04-29 | 2015-11-05 | Infinity Pharmaceuticals, Inc. | Pyrimidine or pyridine derivatives useful as pi3k inhibitors |
| WO2015166373A1 (en) | 2014-04-30 | 2015-11-05 | Pfizer Inc. | Cycloalkyl-linked diheterocycle derivatives |
| US9227978B2 (en) | 2013-03-15 | 2016-01-05 | Araxes Pharma Llc | Covalent inhibitors of Kras G12C |
| WO2016001789A1 (en) | 2014-06-30 | 2016-01-07 | Pfizer Inc. | Pyrimidine derivatives as pi3k inhibitors for use in the treatment of cancer |
| WO2016019280A1 (en) | 2014-07-31 | 2016-02-04 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Human monoclonal antibodies against epha4 and their use |
| EP3009436A1 (en) | 2008-07-08 | 2016-04-20 | Intellikine, LLC | Kinase inhibitors and methods of use |
| WO2016097918A1 (en) | 2014-12-18 | 2016-06-23 | Pfizer Inc. | Pyrimidine and triazine derivatives and their use as axl inhibitors |
| EP3050876A2 (en) | 2009-11-05 | 2016-08-03 | Rhizen Pharmaceuticals S.A. | Kinase modulators |
| US9452215B2 (en) | 2012-02-22 | 2016-09-27 | The Regents Of The University Of Colorado | Bourvadin derivatives and therapeutic uses thereof |
| WO2016178876A2 (en) | 2015-05-01 | 2016-11-10 | Cocrystal Pharma, Inc. | Nucleoside analogs for treatment of the flaviviridae family of viruses and cancer |
| WO2017009751A1 (en) | 2015-07-15 | 2017-01-19 | Pfizer Inc. | Pyrimidine derivatives |
| EP3135692A1 (en) | 2010-06-16 | 2017-03-01 | University of Pittsburgh of the Commonwealth System of Higher Education | Antibodies to endoplasmin and their use |
| EP3135690A1 (en) | 2012-06-26 | 2017-03-01 | Sutro Biopharma, Inc. | Modified fc proteins comprising site-specific non-natural amino acid residues, conjugates of the same, methods of their preparation and methods of their use |
| WO2017058768A1 (en) | 2015-09-28 | 2017-04-06 | Araxes Pharma Llc | Inhibitors of kras g12c mutant proteins |
| WO2017058792A1 (en) | 2015-09-28 | 2017-04-06 | Araxes Pharma Llc | Inhibitors of kras g12c mutant proteins |
| WO2017087528A1 (en) | 2015-11-16 | 2017-05-26 | Araxes Pharma Llc | 2-substituted quinazoline compounds comprising a substituted heterocyclic group and methods of use thereof |
| WO2017096165A1 (en) | 2015-12-03 | 2017-06-08 | Agios Pharmaceuticals, Inc. | Mat2a inhibitors for treating mtap null cancer |
| WO2017132617A1 (en) | 2016-01-27 | 2017-08-03 | Sutro Biopharma, Inc. | Anti-cd74 antibody conjugates, compositions comprising anti-cd74 antibody conjugates and methods of using anti-cd74 antibody conjugates |
| WO2017161002A1 (en) | 2016-03-16 | 2017-09-21 | Kura Oncology, Inc. | Bridged bicyclic inhibitors of menin-mll and methods of use |
| WO2017161028A1 (en) | 2016-03-16 | 2017-09-21 | Kura Oncology, Inc. | Substituted inhibitors of menin-mll and methods of use |
| US9810690B2 (en) | 2015-10-19 | 2017-11-07 | Araxes Pharma Llc | Method for screening inhibitors of Ras |
| WO2017197240A1 (en) | 2016-05-12 | 2017-11-16 | The Regents Of The University Of Michigan | Ash1l inhibitors and methods of treatment therewith |
| US9840516B2 (en) | 2013-10-10 | 2017-12-12 | Araxes Pharma Llc | Substituted quinazolines as inhibitors of KRAS G12C |
| WO2017214269A1 (en) | 2016-06-08 | 2017-12-14 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| US9862701B2 (en) | 2014-09-25 | 2018-01-09 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
| WO2018045379A1 (en) | 2016-09-02 | 2018-03-08 | Dana-Farber Cancer Institute, Inc. | Composition and methods of treating b cell disorders |
| WO2018064510A1 (en) | 2016-09-29 | 2018-04-05 | Araxes Pharma Llc | Inhibitors of kras g12c mutant proteins |
| WO2018068017A1 (en) | 2016-10-07 | 2018-04-12 | Araxes Pharma Llc | Heterocyclic compounds as inhibitors of ras and methods of use thereof |
| WO2018098352A2 (en) | 2016-11-22 | 2018-05-31 | Jun Oishi | Targeting kras induced immune checkpoint expression |
| US9988357B2 (en) | 2015-12-09 | 2018-06-05 | Araxes Pharma Llc | Methods for preparation of quinazoline derivatives |
| WO2018119183A2 (en) | 2016-12-22 | 2018-06-28 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
| US10011600B2 (en) | 2014-09-25 | 2018-07-03 | Araxes Pharma Llc | Methods and compositions for inhibition of Ras |
| WO2018140598A1 (en) | 2017-01-26 | 2018-08-02 | Araxes Pharma Llc | Fused n-heterocyclic compounds and methods of use thereof |
| WO2018140514A1 (en) | 2017-01-26 | 2018-08-02 | Araxes Pharma Llc | 1-(6-(3-hydroxynaphthalen-1-yl)quinazolin-2-yl)azetidin-1-yl)prop-2-en-1-one derivatives and similar compounds as kras g12c inhibitors for the treatment of cancer |
| WO2018140599A1 (en) | 2017-01-26 | 2018-08-02 | Araxes Pharma Llc | Benzothiophene and benzothiazole compounds and methods of use thereof |
| WO2018140600A1 (en) | 2017-01-26 | 2018-08-02 | Araxes Pharma Llc | Fused hetero-hetero bicyclic compounds and methods of use thereof |
| WO2018140512A1 (en) | 2017-01-26 | 2018-08-02 | Araxes Pharma Llc | Fused bicyclic benzoheteroaromatic compounds and methods of use thereof |
| WO2018140513A1 (en) | 2017-01-26 | 2018-08-02 | Araxes Pharma Llc | 1-(3-(6-(3-hydroxynaphthalen-1-yl)benzofuran-2-yl)azetidin-1yl)prop-2-en-1-one derivatives and similar compounds as kras g12c modulators for treating cancer |
| WO2018175746A1 (en) | 2017-03-24 | 2018-09-27 | Kura Oncology, Inc. | Methods for treating hematological malignancies and ewing's sarcoma |
| US10111874B2 (en) | 2014-09-18 | 2018-10-30 | Araxes Pharma Llc | Combination therapies for treatment of cancer |
| WO2018218070A2 (en) | 2017-05-25 | 2018-11-29 | Araxes Pharma Llc | Covalent inhibitors of kras |
| WO2018217651A1 (en) | 2017-05-22 | 2018-11-29 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
| WO2018218069A1 (en) | 2017-05-25 | 2018-11-29 | Araxes Pharma Llc | Quinazoline derivatives as modulators of mutant kras, hras or nras |
| WO2018218071A1 (en) | 2017-05-25 | 2018-11-29 | Araxes Pharma Llc | Compounds and methods of use thereof for treatment of cancer |
| US10144724B2 (en) | 2015-07-22 | 2018-12-04 | Araxes Pharma Llc | Substituted quinazoline compounds and methods of use thereof |
| EP3409669A1 (en) | 2014-06-19 | 2018-12-05 | ARIAD Pharmaceuticals, Inc. | Heteroaryl compounds for kinase inhibition |
| EP3409278A1 (en) | 2011-07-21 | 2018-12-05 | Tolero Pharmaceuticals, Inc. | Heterocyclic protein kinase inhibitors |
| WO2019023316A1 (en) | 2017-07-26 | 2019-01-31 | Sutro Biopharma, Inc. | Methods of using anti-cd74 antibodies and antibody conjugates in treatment of t-cell lymphoma |
| WO2019051291A1 (en) | 2017-09-08 | 2019-03-14 | Amgen Inc. | KRAS G12C INHIBITORS AND METHODS OF USE |
| WO2019055909A1 (en) | 2017-09-18 | 2019-03-21 | Sutro Biopharma, Inc. | Anti-folate receptor alpha antibody conjugates and their uses |
| US10246424B2 (en) | 2015-04-10 | 2019-04-02 | Araxes Pharma Llc | Substituted quinazoline compounds and methods of use thereof |
| WO2019075367A1 (en) | 2017-10-13 | 2019-04-18 | Tolero Pharmaceuticals, Inc. | Pkm2 activators in combination with reactive oxygen species for treatment of cancer |
| WO2019094773A1 (en) | 2017-11-10 | 2019-05-16 | The Regents Of The University Of Michigan | Ash1l inhibitors and methods of treatment therewith |
| WO2019113469A1 (en) | 2017-12-07 | 2019-06-13 | The Regents Of The University Of Michigan | Nsd family inhibitors and methods of treatment therewith |
| US10428064B2 (en) | 2015-04-15 | 2019-10-01 | Araxes Pharma Llc | Fused-tricyclic inhibitors of KRAS and methods of use thereof |
| WO2019213526A1 (en) | 2018-05-04 | 2019-11-07 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
| WO2019213516A1 (en) | 2018-05-04 | 2019-11-07 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
| WO2019217691A1 (en) | 2018-05-10 | 2019-11-14 | Amgen Inc. | Kras g12c inhibitors for the treatment of cancer |
| WO2019232419A1 (en) | 2018-06-01 | 2019-12-05 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
| WO2019236957A1 (en) | 2018-06-07 | 2019-12-12 | The Regents Of The University Of Michigan | Prc1 inhibitors and methods of treatment therewith |
| WO2019241157A1 (en) | 2018-06-11 | 2019-12-19 | Amgen Inc. | Kras g12c inhibitors for treating cancer |
| EP3590932A1 (en) | 2013-03-14 | 2020-01-08 | Tolero Pharmaceuticals, Inc. | Jak2 and alk2 inhibitors and methods for their use |
| WO2020028706A1 (en) | 2018-08-01 | 2020-02-06 | Araxes Pharma Llc | Heterocyclic spiro compounds and methods of use thereof for the treatment of cancer |
| EP3613743A1 (en) | 2008-01-04 | 2020-02-26 | Intellikine, LLC | Processes for the preparation of 1h-pyrazolo[3,4-d]pyrimidin-4-amine derivatives |
| WO2020050890A2 (en) | 2018-06-12 | 2020-03-12 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
| WO2020060944A1 (en) | 2018-09-17 | 2020-03-26 | Sutro Biopharma, Inc. | Combination therapies with anti-folate receptor antibody conjugates |
| WO2020086739A1 (en) | 2018-10-24 | 2020-04-30 | Araxes Pharma Llc | 2-(2-acryloyl-2,6-diazaspiro[3.4]octan-6-yl)-6-(1h-indazol-4-yl)-benzonitrile derivatives and related compounds as inhibitors of g12c mutant kras protein for inhibiting tumor metastasis |
| US10646488B2 (en) | 2016-07-13 | 2020-05-12 | Araxes Pharma Llc | Conjugates of cereblon binding compounds and G12C mutant KRAS, HRAS or NRAS protein modulating compounds and methods of use thereof |
| WO2020102730A1 (en) | 2018-11-16 | 2020-05-22 | Amgen Inc. | Improved synthesis of key intermediate of kras g12c inhibitor compound |
| WO2020106640A1 (en) | 2018-11-19 | 2020-05-28 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
| WO2020106647A2 (en) | 2018-11-19 | 2020-05-28 | Amgen Inc. | Combination therapy including a krasg12c inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers |
| WO2020113071A1 (en) | 2018-11-29 | 2020-06-04 | Araxes Pharma Llc | Compounds and methods of use thereof for treatment of cancer |
| US10689356B2 (en) | 2015-09-28 | 2020-06-23 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
| WO2020132653A1 (en) | 2018-12-20 | 2020-06-25 | Amgen Inc. | Heteroaryl amides useful as kif18a inhibitors |
| WO2020132649A1 (en) | 2018-12-20 | 2020-06-25 | Amgen Inc. | Heteroaryl amides useful as kif18a inhibitors |
| WO2020132651A1 (en) | 2018-12-20 | 2020-06-25 | Amgen Inc. | Kif18a inhibitors |
| WO2020132648A1 (en) | 2018-12-20 | 2020-06-25 | Amgen Inc. | Kif18a inhibitors |
| US10730867B2 (en) | 2015-09-28 | 2020-08-04 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
| US10766865B2 (en) | 2012-10-16 | 2020-09-08 | Sumitomo Dainippon Pharma Oncology, Inc. | PKM2 modulators and methods for their use |
| WO2020180770A1 (en) | 2019-03-01 | 2020-09-10 | Revolution Medicines, Inc. | Bicyclic heterocyclyl compounds and uses thereof |
| WO2020180768A1 (en) | 2019-03-01 | 2020-09-10 | Revolution Medicines, Inc. | Bicyclic heteroaryl compounds and uses thereof |
| WO2020198077A1 (en) | 2019-03-22 | 2020-10-01 | Sumitomo Dainippon Pharma Oncology, Inc. | Compositions comprising pkm2 modulators and methods of treatment using the same |
| US10822312B2 (en) | 2016-03-30 | 2020-11-03 | Araxes Pharma Llc | Substituted quinazoline compounds and methods of use |
| WO2020227105A1 (en) | 2019-05-03 | 2020-11-12 | Sutro Biopharma, Inc. | Anti-bcma antibody conjugates |
| US10835537B2 (en) | 2015-08-03 | 2020-11-17 | Sumitomo Dainippon Pharma Oncology, Inc. | Combination therapies for treatment of cancer |
| US10858343B2 (en) | 2015-09-28 | 2020-12-08 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
| US10875842B2 (en) | 2015-09-28 | 2020-12-29 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
| WO2021003417A1 (en) | 2019-07-03 | 2021-01-07 | Sumitomo Dainippon Pharma Oncology, Inc. | Tyrosine kinase non-receptor 1 (tnk1) inhibitors and uses thereof |
| WO2021026099A1 (en) | 2019-08-02 | 2021-02-11 | Amgen Inc. | Kif18a inhibitors |
| WO2021026101A1 (en) | 2019-08-02 | 2021-02-11 | Amgen Inc. | Kif18a inhibitors |
| WO2021026100A1 (en) | 2019-08-02 | 2021-02-11 | Amgen Inc. | Pyridine derivatives as kif18a inhibitors |
| WO2021026098A1 (en) | 2019-08-02 | 2021-02-11 | Amgen Inc. | Kif18a inhibitors |
| WO2021055728A1 (en) | 2019-09-18 | 2021-03-25 | Merck Sharp & Dohme Corp. | Small molecule inhibitors of kras g12c mutant |
| WO2021067215A1 (en) | 2019-09-30 | 2021-04-08 | Agios Pharmaceuticals, Inc. | Piperidine compounds as menin inhibitors |
| US10975071B2 (en) | 2015-09-28 | 2021-04-13 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
| WO2021081212A1 (en) | 2019-10-24 | 2021-04-29 | Amgen Inc. | Pyridopyrimidine derivatives useful as kras g12c and kras g12d inhibitors in the treatment of cancer |
| WO2021085653A1 (en) | 2019-10-31 | 2021-05-06 | Taiho Pharmaceutical Co., Ltd. | 4-aminobut-2-enamide derivatives and salts thereof |
| WO2021086833A1 (en) | 2019-10-28 | 2021-05-06 | Merck Sharp & Dohme Corp. | Small molecule inhibitors of kras g12c mutant |
| WO2021091967A1 (en) | 2019-11-04 | 2021-05-14 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2021091956A1 (en) | 2019-11-04 | 2021-05-14 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2021092115A1 (en) | 2019-11-08 | 2021-05-14 | Revolution Medicines, Inc. | Bicyclic heteroaryl compounds and uses thereof |
| WO2021091982A1 (en) | 2019-11-04 | 2021-05-14 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2021097207A1 (en) | 2019-11-14 | 2021-05-20 | Amgen Inc. | Improved synthesis of kras g12c inhibitor compound |
| WO2021097212A1 (en) | 2019-11-14 | 2021-05-20 | Amgen Inc. | Improved synthesis of kras g12c inhibitor compound |
| WO2021107160A1 (en) | 2019-11-29 | 2021-06-03 | Taiho Pharmaceutical Co., Ltd. | A compound having inhibitory activity against kras g12d mutation |
| WO2021108683A1 (en) | 2019-11-27 | 2021-06-03 | Revolution Medicines, Inc. | Covalent ras inhibitors and uses thereof |
| US11034710B2 (en) | 2018-12-04 | 2021-06-15 | Sumitomo Dainippon Pharma Oncology, Inc. | CDK9 inhibitors and polymorphs thereof for use as agents for treatment of cancer |
| US11040038B2 (en) | 2018-07-26 | 2021-06-22 | Sumitomo Dainippon Pharma Oncology, Inc. | Methods for treating diseases associated with abnormal ACVR1 expression and ACVR1 inhibitors for use in the same |
| WO2021142026A1 (en) | 2020-01-07 | 2021-07-15 | Revolution Medicines, Inc. | Shp2 inhibitor dosing and methods of treating cancer |
| WO2021155006A1 (en) | 2020-01-31 | 2021-08-05 | Les Laboratoires Servier Sas | Inhibitors of cyclin-dependent kinases and uses thereof |
| WO2021178597A1 (en) | 2020-03-03 | 2021-09-10 | Sutro Biopharma, Inc. | Antibodies comprising site-specific glutamine tags, methods of their preparation and methods of their use |
| US11118233B2 (en) | 2016-05-18 | 2021-09-14 | The University Of Chicago | BTK mutation and ibrutinib resistance |
| WO2021204159A1 (en) | 2020-04-08 | 2021-10-14 | Agios Pharmaceuticals, Inc. | Menin inhibitors and methods of use for treating cancer |
| WO2021207310A1 (en) | 2020-04-08 | 2021-10-14 | Agios Pharmaceuticals, Inc. | Menin inhibitors and methods of use for treating cancer |
| WO2021215544A1 (en) | 2020-04-24 | 2021-10-28 | Taiho Pharmaceutical Co., Ltd. | Kras g12d protein inhibitors |
| WO2021215545A1 (en) | 2020-04-24 | 2021-10-28 | Taiho Pharmaceutical Co., Ltd. | Anticancer combination therapy with n-(1-acryloyl-azetidin-3-yl)-2-((1h-indazol-3-yl)amino)methyl)-1h-imidazole-5-carboxamide inhibitor of kras-g12c |
| WO2021257736A1 (en) | 2020-06-18 | 2021-12-23 | Revolution Medicines, Inc. | Methods for delaying, preventing, and treating acquired resistance to ras inhibitors |
| WO2022014640A1 (en) | 2020-07-15 | 2022-01-20 | 大鵬薬品工業株式会社 | Pyrimidine compound-containing combination to be used in tumor treatment |
| US11236091B2 (en) | 2019-05-21 | 2022-02-01 | Amgen Inc. | Solid state forms |
| US11241414B2 (en) | 2008-03-28 | 2022-02-08 | Neurelis, Inc. | Administration of benzodiazepine compositions |
| US11267885B2 (en) | 2017-01-26 | 2022-03-08 | Zlip Holding Limited | CD47 antigen binding unit and uses thereof |
| US11279694B2 (en) | 2016-11-18 | 2022-03-22 | Sumitomo Dainippon Pharma Oncology, Inc. | Alvocidib prodrugs and their use as protein kinase inhibitors |
| WO2022060583A1 (en) | 2020-09-03 | 2022-03-24 | Revolution Medicines, Inc. | Use of sos1 inhibitors to treat malignancies with shp2 mutations |
| WO2022060836A1 (en) | 2020-09-15 | 2022-03-24 | Revolution Medicines, Inc. | Indole derivatives as ras inhibitors in the treatment of cancer |
| EP4006030A2 (en) | 2015-06-04 | 2022-06-01 | Kura Oncology, Inc. | Methods and compositions for inhibiting the interaction of menin with mll proteins |
| WO2022140427A1 (en) | 2020-12-22 | 2022-06-30 | Qilu Regor Therapeutics Inc. | Sos1 inhibitors and uses thereof |
| US11426404B2 (en) | 2019-05-14 | 2022-08-30 | Amgen Inc. | Dosing of KRAS inhibitor for treatment of cancers |
| US11471456B2 (en) | 2019-02-12 | 2022-10-18 | Sumitomo Pharma Oncology, Inc. | Formulations comprising heterocyclic protein kinase inhibitors |
| WO2022221227A1 (en) | 2021-04-13 | 2022-10-20 | Nuvalent, Inc. | Amino-substituted heterocycles for treating cancers with egfr mutations |
| WO2022235870A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors for the treatment of cancer |
| WO2022235864A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2022235866A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Covalent ras inhibitors and uses thereof |
| US11497756B2 (en) | 2017-09-12 | 2022-11-15 | Sumitomo Pharma Oncology, Inc. | Treatment regimen for cancers that are insensitive to BCL-2 inhibitors using the MCL-1 inhibitor alvocidib |
| WO2022250170A1 (en) | 2021-05-28 | 2022-12-01 | Taiho Pharmaceutical Co., Ltd. | Small molecule inhibitors of kras mutated proteins |
| US11542248B2 (en) | 2017-06-08 | 2023-01-03 | Kura Oncology, Inc. | Methods and compositions for inhibiting the interaction of menin with MLL proteins |
| WO2023060253A1 (en) | 2021-10-08 | 2023-04-13 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2023056589A1 (en) | 2021-10-08 | 2023-04-13 | Servier Pharmaceuticals Llc | Menin inhibitors and methods of use for treating cancer |
| US11649251B2 (en) | 2017-09-20 | 2023-05-16 | Kura Oncology, Inc. | Substituted inhibitors of menin-MLL and methods of use |
| WO2023114954A1 (en) | 2021-12-17 | 2023-06-22 | Genzyme Corporation | Pyrazolopyrazine compounds as shp2 inhibitors |
| EP4227307A1 (en) | 2022-02-11 | 2023-08-16 | Genzyme Corporation | Pyrazolopyrazine compounds as shp2 inhibitors |
| US11746103B2 (en) | 2020-12-10 | 2023-09-05 | Sumitomo Pharma Oncology, Inc. | ALK-5 inhibitors and uses thereof |
| WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
| US11793802B2 (en) | 2019-03-20 | 2023-10-24 | Sumitomo Pharma Oncology, Inc. | Treatment of acute myeloid leukemia (AML) with venetoclax failure |
| WO2023211812A1 (en) | 2022-04-25 | 2023-11-02 | Nested Therapeutics, Inc. | Heterocyclic derivatives as mitogen-activated protein kinase (mek) inhibitors |
| WO2023240263A1 (en) | 2022-06-10 | 2023-12-14 | Revolution Medicines, Inc. | Macrocyclic ras inhibitors |
| US11858925B2 (en) | 2020-07-10 | 2024-01-02 | The Regents Of The University Of Michigan | GAS41 inhibitors and methods of use thereof |
| WO2024006542A1 (en) | 2022-06-30 | 2024-01-04 | Sutro Biopharma, Inc. | Anti-ror1 antibodies and antibody conjugates, compositions comprising anti-ror1 antibodies or antibody conjugates, and methods of making and using anti-ror1 antibodies and antibody conjugates |
| WO2024010925A2 (en) | 2022-07-08 | 2024-01-11 | Nested Therapeutics, Inc. | Mitogen-activated protein kinase (mek) inhibitors |
| US11931420B2 (en) | 2021-04-30 | 2024-03-19 | Celgene Corporation | Combination therapies using an anti-BCMA antibody drug conjugate (ADC) in combination with a gamma secretase inhibitor (GSI) |
| WO2024081916A1 (en) | 2022-10-14 | 2024-04-18 | Black Diamond Therapeutics, Inc. | Methods of treating cancers using isoquinoline or 6-aza-quinoline derivatives |
| WO2024206858A1 (en) | 2023-03-30 | 2024-10-03 | Revolution Medicines, Inc. | Compositions for inducing ras gtp hydrolysis and uses thereof |
| WO2024211663A1 (en) | 2023-04-07 | 2024-10-10 | Revolution Medicines, Inc. | Condensed macrocyclic compounds as ras inhibitors |
| WO2024211712A1 (en) | 2023-04-07 | 2024-10-10 | Revolution Medicines, Inc. | Condensed macrocyclic compounds as ras inhibitors |
| WO2024216016A1 (en) | 2023-04-14 | 2024-10-17 | Revolution Medicines, Inc. | Crystalline forms of a ras inhibitor |
| WO2024216048A1 (en) | 2023-04-14 | 2024-10-17 | Revolution Medicines, Inc. | Crystalline forms of ras inhibitors, compositions containing the same, and methods of use thereof |
| WO2024226579A1 (en) | 2023-04-24 | 2024-10-31 | Nested Therapeutics, Inc. | Heterocyclic derivative as mitogen-activated protein kinase (mek) inhibitor |
| WO2024229406A1 (en) | 2023-05-04 | 2024-11-07 | Revolution Medicines, Inc. | Combination therapy for a ras related disease or disorder |
| WO2025034702A1 (en) | 2023-08-07 | 2025-02-13 | Revolution Medicines, Inc. | Rmc-6291 for use in the treatment of ras protein-related disease or disorder |
| WO2025043187A1 (en) | 2023-08-24 | 2025-02-27 | Otsuka Pharmaceutical Co., Ltd. | Fixed dose combinations of cedazuridine and azacitidine |
| WO2025080946A2 (en) | 2023-10-12 | 2025-04-17 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2025081117A2 (en) | 2023-10-13 | 2025-04-17 | Sutro Biopharma, Inc. | Anti-tissue factor antibodies and antibody conjugates, compositions comprising anti-tissue factor antibodies or antibody conjugates, and methods of making and using anti-tissue factor antibodies and antibody conjugates |
| WO2025085748A1 (en) | 2023-10-20 | 2025-04-24 | Merck Sharp & Dohme Llc | Small molecule inhibitors of kras proteins |
| WO2025090905A1 (en) | 2023-10-26 | 2025-05-01 | Nested Therapeutics, Inc. | Crystalline forms of 3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-7-[(3-fluoro-2-pyridyl)oxy]-4-methyl-chromen-2-one |
| US12338261B2 (en) | 2015-05-18 | 2025-06-24 | Sumitomo Pharma Oncology, Inc. | Alvocidib prodrugs having increased bioavailability |
| WO2025137507A1 (en) | 2023-12-22 | 2025-06-26 | Regor Pharmaceuticals, Inc. | Sos1 inhibitors and uses thereof |
| EP4585268A2 (en) | 2015-09-14 | 2025-07-16 | Twelve Therapeutics, Inc. | Solid forms of isoquinolinone derivatives, process of making, compositions comprising, and methods of using the same |
| US12440491B2 (en) | 2023-06-23 | 2025-10-14 | Amgen Inc. | KRAS G12C inhibitors and methods of using the same |
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7141607B1 (en) | 2000-03-10 | 2006-11-28 | Insite Vision Incorporated | Methods and compositions for treating and inhibiting retinal neovascularization |
| US20010053764A1 (en) | 2000-05-12 | 2001-12-20 | Sims John E. | Interleukin-1 inhibitors in the treatment of diseases |
| TWI318881B (en)* | 2001-09-27 | 2010-01-01 | ||
| CA2471814C (en)* | 2001-12-27 | 2011-03-15 | Sumitomo Pharmaceuticals Co., Ltd. | Hydroxamic acid derivative and mmp inhibitor containing the same as active ingredient |
| DE60327432D1 (en)* | 2002-05-29 | 2009-06-10 | Merck & Co Inc | USEFUL COMPOUNDS FOR THE TREATMENT OF ANTHRAX AND INHIBITION OF THE LETAL FACTOR |
| US20040186160A1 (en)* | 2002-12-13 | 2004-09-23 | Sugen, Inc. | Hexahydro-cyclohepta-pyrrole oxindole as potent kinase inhibitors |
| WO2004087152A1 (en)* | 2003-04-03 | 2004-10-14 | Pfizer Inc. | Dosage forms comprising ag013736 |
| DE10320453A1 (en)* | 2003-05-08 | 2004-11-25 | Morphochem AG Aktiengesellschaft für kombinatorische Chemie | New Actinonin Bioisosteres |
| US7892563B2 (en) | 2003-05-20 | 2011-02-22 | Wyeth Holdings Corporation | Methods for treatment of severe acute respiratory syndrome (SARS) |
| EP1660503A1 (en)* | 2003-08-29 | 2006-05-31 | Pfizer Inc. | Naphthalene carboxamides and their derivatives useful as new anti-angiogenic agents |
| GB0326546D0 (en)* | 2003-11-14 | 2003-12-17 | Amersham Plc | Inhibitor imaging agents |
| CA2547283C (en)* | 2003-11-26 | 2010-11-09 | Pfizer Products Inc. | Aminopyrazole derivatives as gsk-3 inhibitors |
| JP2007530045A (en)* | 2004-03-23 | 2007-11-01 | アムジエン・インコーポレーテツド | Human OX40L (CD134L) specific monoclonal antibody |
| BRPI0509580A (en)* | 2004-03-30 | 2007-11-27 | Pfizer Prod Inc | signal transduction inhibitor combinations |
| JP2008510792A (en)* | 2004-08-26 | 2008-04-10 | ファイザー・インク | Amino heteroaryl compounds as protein tyrosine kinase inhibitors |
| GEP20094845B (en)* | 2004-08-26 | 2009-11-25 | Pfizer | Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors |
| US20060107555A1 (en)* | 2004-11-09 | 2006-05-25 | Curtis Marc D | Universal snow plow adapter |
| US20100003276A1 (en)* | 2004-12-07 | 2010-01-07 | Hermes Jeffery D | Methods for treating anthrax and inhibiting lethal factor |
| US8509487B2 (en)* | 2007-04-19 | 2013-08-13 | Avago Technologies General Ip (Singapore) Pte. Ltd. | System and method for optically measuring a parameter of an object |
| JP2010526822A (en)* | 2007-05-07 | 2010-08-05 | クエスター ファーマシューティカルズ，インク． | Nasal administration of benzodiazepines |
| EP2671891A3 (en) | 2008-06-27 | 2014-03-05 | Amgen Inc. | Ang-2 inhibition to treat multiple sclerosis |
| WO2016054491A1 (en) | 2014-10-03 | 2016-04-07 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| BR112017022666A8 (en) | 2015-04-20 | 2022-10-18 | Tolero Pharmaceuticals Inc | PREPARING RESPONSE TO ALVOCIDIB BY MITOCHONDRIAL PROFILING |
| WO2016197027A1 (en) | 2015-06-04 | 2016-12-08 | Kura Oncology, Inc. | Methods and compositions for inhibiting the interaction of menin with mll proteins |
| CN110234659A (en) | 2016-12-19 | 2019-09-13 | 特雷罗药物股份有限公司 | Analytical peptide and method for sensitivity analysis |
| EP3773591A4 (en) | 2018-04-05 | 2021-12-22 | Sumitomo Dainippon Pharma Oncology, Inc. | AXL KINASE INHIBITORS AND THEIR USES |
| US12311033B2 (en) | 2023-05-31 | 2025-05-27 | Capstan Therapeutics, Inc. | Lipid nanoparticle formulations and compositions |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990005719A1 (en)* | 1988-11-23 | 1990-05-31 | British Bio-Technology Limited | Hydroxamic acid based collagenase inhibitors |
| EP0606046A1 (en)* | 1993-01-06 | 1994-07-13 | Ciba-Geigy Ag | Arylsulfonamido-substituted hydroxamic acids |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56110665A (en)* | 1980-02-08 | 1981-09-01 | Yamanouchi Pharmaceut Co Ltd | Sulfamoyl-substituted phenetylamine derivative and its preparation |
| JPH10501806A (en)* | 1994-06-22 | 1998-02-17 | ブリティッシュ バイオテック ファーマシューティカルズ リミテッド | Metalloproteinase inhibitors |
| JPH11511137A (en)* | 1995-08-08 | 1999-09-28 | ファイブロゲン，インコーポレーテッド | C-proteinase inhibitors for treating diseases associated with collagen overproduction |
- 1995
- 1995-03-07USUS08/894,873patent/US5863949A/ennot_activeExpired - Fee Related
- 1996
- 1996-03-04ILIL11734396Apatent/IL117343A/ennot_activeIP Right Cessation
- 1996-03-04PEPE1996000146Apatent/PE28797A1/ennot_activeApplication Discontinuation
- 1996-03-07PTPT96907134Tpatent/PT813520E/enunknown
- 1996-03-07ATAT96907134Tpatent/ATE211131T1/ennot_activeIP Right Cessation
- 1996-03-07JPJP52691896Apatent/JP3753737B2/ennot_activeExpired - Fee Related
- 1996-03-07MYMYPI96000841Apatent/MY113586A/enunknown
- 1996-03-07TRTR97/00913Tpatent/TR199700913T1/enunknown
- 1996-03-07KRKR1019970706227Apatent/KR100269046B1/ennot_activeExpired - Fee Related
- 1996-03-07FIFI973613Apatent/FI973613L/ennot_activeIP Right Cessation
- 1996-03-07ZAZA9601876Apatent/ZA961876B/enunknown
- 1996-03-07ESES96907134Tpatent/ES2169794T3/ennot_activeExpired - Lifetime
- 1996-03-07RURU97116727Apatent/RU2145597C1/ennot_activeIP Right Cessation
- 1996-03-07DKDK96907134Tpatent/DK0813520T3/enactive
- 1996-03-07MXMX9706850Apatent/MX9706850A/ennot_activeIP Right Cessation
- 1996-03-07CZCZ19972782Apatent/CZ291106B6/ennot_activeIP Right Cessation
- 1996-03-07PLPL96322131Apatent/PL184158B1/ennot_activeIP Right Cessation
- 1996-03-07DEDE69618179Tpatent/DE69618179T2/ennot_activeExpired - Fee Related
- 1996-03-07CNCN96193213Apatent/CN1122662C/ennot_activeExpired - Fee Related
- 1996-03-07HUHU9800462Apatent/HUP9800462A3/enunknown
- 1996-03-07WOPCT/US1996/002679patent/WO1996027583A1/enactiveIP Right Grant
- 1996-03-07AUAU50293/96Apatent/AU707510B2/ennot_activeCeased
- 1996-03-07NZNZ303860Apatent/NZ303860A/enunknown
- 1996-03-07EPEP96907134Apatent/EP0813520B1/ennot_activeExpired - Lifetime
- 1996-03-07CACA002214720Apatent/CA2214720C/ennot_activeExpired - Fee Related
- 1996-03-07BRBR9607362Apatent/BR9607362A/ennot_activeApplication Discontinuation
- 1996-03-08COCO96011441Apatent/CO4700432A1/enunknown
- 1996-03-08ARARP960101684Apatent/AR003935A1/enunknown
- 1996-04-19TWTW085104697Apatent/TW346488B/enactive
- 1997
- 1997-09-05NONO19974103Apatent/NO313752B1/ennot_activeIP Right Cessation
- 2001
- 2001-03-23CNCN01111743Apatent/CN1316419A/enactivePending
- 2002
- 2002-03-25HKHK02102259.0Apatent/HK1041254A1/enunknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990005719A1 (en)* | 1988-11-23 | 1990-05-31 | British Bio-Technology Limited | Hydroxamic acid based collagenase inhibitors |
| EP0606046A1 (en)* | 1993-01-06 | 1994-07-13 | Ciba-Geigy Ag | Arylsulfonamido-substituted hydroxamic acids |
Cited By (552)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5817822A (en)* | 1994-06-24 | 1998-10-06 | Novartis Corporation | Certain alpha-azacycloalkyl substituted arylsulfonamido acetohydroxamic acids |
| US6153757A (en)* | 1995-12-08 | 2000-11-28 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors and intermediates useful for their preparation |
| US5770624A (en)* | 1995-12-15 | 1998-06-23 | Novartis Corp. | Certain alpha-substituted arylsulfonamido acetohydroxamic acids |
| US6153609A (en)* | 1996-08-23 | 2000-11-28 | Pfizer Inc | Arylsulfonylamino hydroxamic acid derivatives |
| WO1998007697A1 (en)* | 1996-08-23 | 1998-02-26 | Pfizer Inc. | Arylsulfonylamino hydroxamic acid derivatives |
| WO1998015525A1 (en)* | 1996-10-07 | 1998-04-16 | Sumitomo Pharmaceuticals Co., Ltd. | Hydroxamic acids |
| US6498167B2 (en) | 1996-10-16 | 2002-12-24 | American Cyanamid Company | Preparation and use of ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors |
| WO1998016503A3 (en)* | 1996-10-16 | 1998-05-28 | American Cyanamid Co | The preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase and tace inhibitors |
| US6548524B2 (en) | 1996-10-16 | 2003-04-15 | American Cyanamid Company | Preparation and use of ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and TACE inhibitors |
| US6534491B2 (en) | 1996-10-16 | 2003-03-18 | American Cyanamid Company | Preparation and use of ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors |
| US5977408A (en)* | 1996-10-16 | 1999-11-02 | American Cyanamid Company | Preparation and use of β-sulfonamido hydroxamic acids as matrix metalloproteinase and TACE inhibitors |
| US6228869B1 (en) | 1996-10-16 | 2001-05-08 | American Cyanamid Company | Ortho-sulfonamido bicyclic hydroxamic acids as matrix metalloproteinase and TACE inhibitors |
| US6197795B1 (en) | 1996-10-16 | 2001-03-06 | American Cyanamid Company | Preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors |
| US5929097A (en)* | 1996-10-16 | 1999-07-27 | American Cyanamid Company | Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase and tace inhibitors |
| US6162814A (en)* | 1996-10-16 | 2000-12-19 | American Cyanamid Company | Preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metaloproteinase and tace inhibitors |
| US5962481A (en)* | 1996-10-16 | 1999-10-05 | American Cyanamid Company | Preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors |
| US6162821A (en)* | 1996-10-16 | 2000-12-19 | American Home Products Corporation | Preparation and use of ortho-sulfonamide heteroarly hydroxamic acids as matrix metalloproteinase and TACE inhibitors |
| US6022873A (en)* | 1996-10-19 | 2000-02-08 | British Biotech Pharmaceuticals Limited | Metalloproteinase inhibitors |
| US5804593A (en)* | 1996-10-22 | 1998-09-08 | Pharmacia & Upjohn Company | α-Amino sulfonyl hydroxamic acids as matrix metalloproteinase inhibitors |
| US6495699B2 (en) | 1996-10-24 | 2002-12-17 | Agouron Pharmaceuticals Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them, and their use |
| US6008243A (en)* | 1996-10-24 | 1999-12-28 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them, and their use |
| WO1998031664A1 (en)* | 1997-01-17 | 1998-07-23 | Pharmacia & Upjohn Company | Bis-sulfonomides hydroxamic acids as mmp inhibitors |
| US5859061A (en)* | 1997-01-17 | 1999-01-12 | Pharmacia & Upjohn Company | Bis-sulfonamides hydroxamic acids as MMP inhibitors |
| US6143744A (en)* | 1997-01-23 | 2000-11-07 | Syntex (U.S.A.) Inc. | Sulfamide-metalloprotease inhibitors |
| US5998412A (en)* | 1997-01-23 | 1999-12-07 | Syntex (U.S.A.) Inc. | Sulfamide-metalloprotease inhibitors |
| US6376506B1 (en) | 1997-01-23 | 2002-04-23 | Syntex (U.S.A.) Llc | Sulfamide-metalloprotease inhibitors |
| CN1113862C (en)* | 1997-02-03 | 2003-07-09 | 辉瑞产品公司 | Arylsulfonylamino hydroxamic acid derivs |
| US6303636B1 (en) | 1997-02-03 | 2001-10-16 | Pfizer Inc | Arylsulfonylamino hydroxamic acid derivatives |
| AP826A (en)* | 1997-02-03 | 2000-04-28 | Pfizer Prod Inc | Arysulfonylamino hydroxamic acid derivatives. |
| WO1998033768A1 (en)* | 1997-02-03 | 1998-08-06 | Pfizer Products Inc. | Arylsulfonylamino hydroxamic acid derivatives |
| EP0977745A4 (en)* | 1997-03-04 | 2000-05-31 | Monsanto Co | Thioaryl sulfonamide hydroxamic acid compounds |
| US6306892B1 (en) | 1997-03-25 | 2001-10-23 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them, and their use |
| US6174915B1 (en) | 1997-03-25 | 2001-01-16 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
| US5985900A (en)* | 1997-04-01 | 1999-11-16 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
| WO1998043963A1 (en)* | 1997-04-01 | 1998-10-08 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
| EP0877018A1 (en)* | 1997-05-09 | 1998-11-11 | Hoechst Aktiengesellschaft | Sulfonylaminocarboxylic acids |
| US7160903B2 (en) | 1997-05-09 | 2007-01-09 | Sanofi-Aventis Deutschland Gmbh | Sulfonylaminocarboxylic acids |
| US6355673B1 (en) | 1997-05-09 | 2002-03-12 | Aventis Pharma Deutschland Gmbh | Substituted diaminocarboxylic acids |
| US6159995A (en)* | 1997-05-09 | 2000-12-12 | Aventis Pharma Deutschland Gmbh | Substituted diaminocarboxylic acids |
| US6451824B1 (en) | 1997-05-09 | 2002-09-17 | Aventis Pharma Deutschland Gmbh | Sulfonylaminocarboxylic acids |
| EP0877019A1 (en)* | 1997-05-09 | 1998-11-11 | Hoechst Aktiengesellschaft | Substituted diaminocarboxylic acid |
| WO1998050348A1 (en)* | 1997-05-09 | 1998-11-12 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
| US5962471A (en)* | 1997-05-13 | 1999-10-05 | Hoechst Aktiengesellschaft | Substituted 6- and 7-aminotetrahydroisoquinolinecarboxylic acids |
| AP1220A (en)* | 1997-08-08 | 2003-10-24 | Pfizer Prod Inc | Aryloxyarylsulfonylamino hydroxamic acid derivatives. |
| EP0895988A1 (en)* | 1997-08-08 | 1999-02-10 | Pfizer Products Inc. | Arylsulfonylamino hydroxamic acid derivatives |
| WO1999007675A1 (en)* | 1997-08-08 | 1999-02-18 | Pfizer Products Inc. | Aryloxyarylsulfonylamino hydroxamic acid derivatives |
| AU730248B2 (en)* | 1997-08-08 | 2001-03-01 | Pfizer Products Inc. | Aryloxyarylsulfonylamino hydroxamic acid derivatives |
| US6214872B1 (en)* | 1997-08-08 | 2001-04-10 | Pfizer Inc. | Aryloxyarylsulfonylamino hydroxamic acid derivatives |
| EP1415984A1 (en)* | 1997-08-08 | 2004-05-06 | Pfizer Products Inc. | Aryloxyarylsulfonylamino hydroxamic acid derivatives |
| US6130220A (en)* | 1997-10-16 | 2000-10-10 | Syntex (Usa) Inc. | Sulfamide-metalloprotease inhibitors |
| JP3479511B2 (en) | 1998-04-10 | 2003-12-15 | ファイザー・プロダクツ・インク | Method for alkylating hindered sulfonamides useful in the manufacture of matrix metalloproteinase inhibitors |
| WO1999052910A1 (en)* | 1998-04-10 | 1999-10-21 | Pfizer Products Inc. | Bicyclic hydroxamic acid derivatives |
| US6229025B1 (en) | 1998-04-10 | 2001-05-08 | Pfizer Inc | Process for alkylating hindered sulfonamides |
| US6288246B1 (en) | 1998-04-10 | 2001-09-11 | Pfizer Inc | Process for preparing hydroxamic acids |
| EP0952148A1 (en)* | 1998-04-10 | 1999-10-27 | Pfizer Products Inc. | Cyclobutyl-aryloxyarylsulfonylamino hydroxamic acid derivatives |
| US6114568A (en)* | 1998-04-10 | 2000-09-05 | Pfizer Inc. | Process for alkylating hindered sulfonamides useful in the production of matrix metalloproteinase inhibitors |
| US6118016A (en)* | 1998-04-10 | 2000-09-12 | Pfizer Inc. | Process for preparing phenoxyphenylsulfonyl halides |
| AP1095A (en)* | 1998-04-10 | 2002-08-26 | Pfizer Prod Inc | Process for alkylating hindered sulfonamides. |
| EP0949245A1 (en)* | 1998-04-10 | 1999-10-13 | Pfizer Products Inc. | Process for alkylating hindered sulfonamides |
| AP1047A (en)* | 1998-04-10 | 2002-02-28 | Pfizer Prod Inc | Bicycle hydroxamic acid derivatives. |
| US6156798A (en)* | 1998-04-10 | 2000-12-05 | Pfizer Inc | Cyclobutyl-aryloxyarylsulfonylamino hydroxamic acid derivatives |
| AP1203A (en)* | 1998-04-10 | 2003-09-05 | Pfizer Prod Inc | Process for preapring hydroxamic acids. |
| WO1999052862A1 (en)* | 1998-04-10 | 1999-10-21 | Pfizer Products Inc. | Process for alkylating hindered sulfonamides useful in the production of matrix metalloproteinase inhibitors |
| US6235727B1 (en) | 1998-07-16 | 2001-05-22 | Aventis Pharma Deutschland Gmbh | Sulfonylaminophosphinic and sulfonylaminophosphinic acid derivatives, methods for their preparation and use |
| US6500811B2 (en) | 1998-07-16 | 2002-12-31 | Aventis Pharma Deutschland Gmbh | Sulfonylaminophosphinic and sulfonylaminophosphonic acid derivatives, methods for their preparation and use |
| US6107337A (en)* | 1998-08-06 | 2000-08-22 | Pfizer Inc. | Arylsulfonylamino hydroxamic acid derivatives |
| CZ302291B6 (en)* | 1998-11-06 | 2011-02-09 | Sanofi - Aventis Deutschland GmbH | Arylsulfonylamino acid compound, process for its preparation and pharmaceutical composition in which the compound is comprised |
| US6201130B1 (en) | 1998-11-06 | 2001-03-13 | Aventis Pharma Duetschland Gmbh | N-arylsulfonylamino acid omega-amides |
| RU2228330C2 (en)* | 1998-11-06 | 2004-05-10 | Авентис Фарма Дойчланд Гмбх | N-arylsulfonyl amino acid omega-amides |
| US6858598B1 (en) | 1998-12-23 | 2005-02-22 | G. D. Searle & Co. | Method of using a matrix metalloproteinase inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia |
| US6716833B2 (en) | 1999-01-27 | 2004-04-06 | Wyeth Holdings Corporation | Acetylenic α-amino acid-based sulfonamide hydroxamic acid tace inhibitors |
| US6277885B1 (en) | 1999-01-27 | 2001-08-21 | American Cyanamid Company | Acetylenic aryl sulfonamide and phosphinic acid amide hydroxamic acid TACE inhibitors |
| US6946473B2 (en) | 1999-01-27 | 2005-09-20 | Wyeth Holdings Corporation | Preparation and use of acetylenic ortho-sulfonamido and phosphinic acid amido bicyclic heteroaryl hydroxamic acids as TACE inhibitors |
| US6825354B2 (en) | 1999-01-27 | 2004-11-30 | Wyeth Holdings Corporation | Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase and TACE inhibitors |
| US6812227B2 (en) | 1999-01-27 | 2004-11-02 | Wyeth Holdings Corporation | Acetylenic α-amino acid-based sulfonamide hydroxamic acid tace inhibitors |
| US6762178B2 (en) | 1999-01-27 | 2004-07-13 | Wyeth Holdings Corporation | Acetylenic aryl sulfonamide and phosphinic acid amide hydroxamic acid TACE inhibitors |
| US6358980B1 (en) | 1999-01-27 | 2002-03-19 | American Cyanamid Company | Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase/tace inhibitors |
| US6340691B1 (en) | 1999-01-27 | 2002-01-22 | American Cyanamid Company | Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase and tace inhibitors |
| US6326516B1 (en) | 1999-01-27 | 2001-12-04 | American Cyanamid Company | Acetylenic β-sulfonamido and phosphinic acid amide hydroxamic acid TACE inhibitors |
| US6200996B1 (en) | 1999-01-27 | 2001-03-13 | American Cyanamid Company | Heteroaryl acetylenic sulfonamide and phosphinic acid amide hydroxamic acid tace inhibitors |
| US6313123B1 (en) | 1999-01-27 | 2001-11-06 | American Cyanamid Company | Acetylenic sulfonamide thiol tace inhibitors |
| US6753337B2 (en) | 1999-01-27 | 2004-06-22 | Wyeth Holdings Corporation | Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase/tace inhibitors |
| US6225311B1 (en) | 1999-01-27 | 2001-05-01 | American Cyanamid Company | Acetylenic α-amino acid-based sulfonamide hydroxamic acid tace inhibitors |
| US6506936B1 (en) | 1999-02-25 | 2003-01-14 | Fibrogen, Inc. | N-substituted arylsulfonylamino hydroxamic acids useful as inhibitors of c-proteinase and for treating or preventing disorders related to unregulated collagen production |
| WO2000063165A1 (en)* | 1999-04-19 | 2000-10-26 | Fujisawa Pharmaceutical Co., Ltd. | Mmp inhibitor |
| US8455497B2 (en) | 1999-06-11 | 2013-06-04 | Vertex Pharmaceuticals Incorporated | Inhibitors of aspartyl protease |
| US6417229B1 (en) | 1999-10-01 | 2002-07-09 | Pfizer Inc | α-sulfonylamino hydroxamic acid inhibitors of matrix metalloproteinases for the treatment of peripheral or central nervous system disorders |
| EP1088550A1 (en)* | 1999-10-01 | 2001-04-04 | Pfizer Products Inc. | alpha-sulfonylamino hydroxamic acid inhibitors of matrix metallo-proteinases for the treatment of peripheral or central nervous system disorders |
| EP3100730A1 (en) | 1999-11-11 | 2016-12-07 | OSI Pharmaceuticals, LLC | N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine for use in the treatment of nsclc |
| EP2292233A2 (en) | 1999-11-11 | 2011-03-09 | OSI Pharmaceuticals, Inc. | Pharmaceutical uses of N-(3-Ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine |
| US6825352B2 (en) | 2000-02-25 | 2004-11-30 | Wyeth | Preparation and use of ortho-sulfonamido arylhydroxamic acids as matrix metalloproteinase inhibitors |
| US7470794B2 (en) | 2000-02-25 | 2008-12-30 | Wyeth | Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase inhibitors |
| US6465508B1 (en) | 2000-02-25 | 2002-10-15 | Wyeth | Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase inhibitors |
| US6458822B2 (en) | 2000-03-13 | 2002-10-01 | Pfizer Inc. | 2-oxo-imidazolidine-4-carboxylic acid hydroxamide compounds that inhibit matrix metalloproteinases |
| US7037498B2 (en) | 2001-01-05 | 2006-05-02 | Abgenix, Inc. | Antibodies to insulin-like growth factor I receptor |
| US7815907B2 (en) | 2001-01-05 | 2010-10-19 | Amgen Fremont Inc. | Antibodies to insulin-like growth factor I receptor |
| US9234041B2 (en) | 2001-01-05 | 2016-01-12 | Pfizer Inc. | Antibodies to insulin-like growth factor I receptor |
| EP2796468A2 (en) | 2001-01-05 | 2014-10-29 | Pfizer Inc | Antibodies to insulin-like growth factor I receptor |
| US7700742B2 (en) | 2001-01-05 | 2010-04-20 | Amgen Fremont | Antibodies to insulin-like growth factor I receptor |
| EP2194067A2 (en) | 2001-01-05 | 2010-06-09 | Pfizer Inc. | Antibodies to insulin-like growth factor I receptor (IGF-IR) |
| US7982024B2 (en) | 2001-01-05 | 2011-07-19 | Amgen Fremont Inc. | Antibodies to insulin-like growth factor I receptor |
| US7427631B2 (en) | 2001-03-15 | 2008-09-23 | Astrazeneca Ab | Metalloproteinase inhibitors |
| US7754750B2 (en) | 2001-03-15 | 2010-07-13 | Astrazeneca Ab | Metalloproteinase inhibitors |
| US7666892B2 (en) | 2001-03-15 | 2010-02-23 | Astrazeneca Ab | Metalloproteinase inhibitors |
| US7368465B2 (en) | 2001-03-15 | 2008-05-06 | Astrazeneca Ab | Metalloproteinase inhibitors |
| US6995171B2 (en) | 2001-06-21 | 2006-02-07 | Agouron Pharmaceuticals, Inc. | Bicyclic pyrimidine and pyrimidine derivatives useful as anticancer agents |
| US7282496B2 (en) | 2001-11-01 | 2007-10-16 | Wyeth Holdings Corporation | Allenic aryl sulfonamide hydroxamic acids as matrix metalloproteinase and TACE inhibitors |
| US7132434B2 (en) | 2001-11-07 | 2006-11-07 | Astrazeneca Ab | Metalloproteinase inhibitors |
| WO2003040098A1 (en)* | 2001-11-07 | 2003-05-15 | Astrazeneca Ab | Novel metalloproteinase inhibitors |
| EP2343086A2 (en) | 2001-11-09 | 2011-07-13 | Pfizer Products Inc. | Antibodies to CD40 |
| US7288251B2 (en) | 2001-11-09 | 2007-10-30 | Abgenix, Inc. | Antibodies to CD40 |
| US7618633B2 (en) | 2001-11-09 | 2009-11-17 | Amgen Fremont Inc. | Antibodies that bind CD40 and methods of treating cancer and enhancing immune responses |
| US7338660B2 (en) | 2001-11-09 | 2008-03-04 | Abgenix, Inc. | Methods of treating cancer and enhancing immune responses with antibodies that bind CD40 |
| US7626012B2 (en) | 2001-11-09 | 2009-12-01 | Amgen Fremont Inc. | Nucleic acid molecules which encode antibodies that bind CD40 |
| US7563442B2 (en) | 2001-11-09 | 2009-07-21 | Abgenix, Inc. | Antibodies to CD40 and methods of treating cancer and enhancing immune responses |
| RU2284185C2 (en)* | 2002-01-08 | 2006-09-27 | Маттиас Рат | Composition inhibiting matrix metalloproteinases for treatment of neoplasm diseases |
| US6833456B2 (en) | 2002-03-01 | 2004-12-21 | Agouron Pharmaceuticals, Inc. | Indolyl-urea derivatives of thienopyridines useful as antiangiogenic agents, and methods for their use |
| US6716853B2 (en) | 2002-03-02 | 2004-04-06 | Aventis Pharma Deutschland Gmbh | Cyclic N-substituted alpha-imino carboxylic acids for selective inhibition of collogenase |
| EP2130537A1 (en) | 2002-03-13 | 2009-12-09 | Array Biopharma, Inc. | N3 alkylated benzimidazole derivatives as mek inhibitors |
| EP2275102A1 (en) | 2002-03-13 | 2011-01-19 | Array Biopharma, Inc. | N3 alkylated benzimidazole derivatives as MEK inhibitors |
| EP3000810A1 (en) | 2002-03-13 | 2016-03-30 | Array Biopharma, Inc. | N3 alkylated benzimidazole derivative as mek inhibitor |
| EP2130536A1 (en) | 2002-03-13 | 2009-12-09 | Array Biopharma, Inc. | N3 alkylated benzimidazole derivatives as mek inhibitors |
| US7022846B2 (en) | 2002-06-10 | 2006-04-04 | Agouron Pharmaceuticals, Inc. | Metabolites of prinomastat and their synthesis |
| US6869962B2 (en) | 2002-06-14 | 2005-03-22 | Agouron Pharmaceuticals, Inc. | Benzofused heterozryl amide derivatives of thienopyridines useful as therapeutic agents, pharmaceutical compositions including the same, and methods for their use |
| US7045528B2 (en) | 2002-06-14 | 2006-05-16 | Agouron Pharmaceuticals, Inc. | Benzofused heterozryl amide derivatives of thienopyridines useful as therapeutic agents, pharmaceutical compositions including the same, and methods for their use |
| US7662845B2 (en) | 2002-08-27 | 2010-02-16 | Astrazeneca Ab | 2,5-Dioxoimidazolidin-4-yl acetamides and analogues as inhibitors of metalloproteinase MMP12 |
| US7354940B2 (en) | 2002-08-27 | 2008-04-08 | Astrazeneca Ab | 2,5-dioxoimidazolidin-4-yl acetamines and analogues as inhibitors of metalloproteinase mmp12 |
| US7053107B2 (en) | 2002-12-19 | 2006-05-30 | Agouron Pharmaceuticals, Inc. | Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use |
| US7485667B2 (en) | 2002-12-23 | 2009-02-03 | Wyeth Holdings Corporation | Acetylenic aryl sulfonate hydroxamic acid tace and matrix metalloproteinase inhibitors |
| US7199155B2 (en) | 2002-12-23 | 2007-04-03 | Wyeth Holdings Corporation | Acetylenic aryl sulfonate hydroxamic acid TACE and matrix metalloproteinase inhibitors |
| US7772270B2 (en) | 2003-01-03 | 2010-08-10 | Sanofi-Aventis Deutschland Gmbh | Imino acid derivatives as inhibitors of matrix metalloproteinases |
| EP2476667A2 (en) | 2003-02-26 | 2012-07-18 | Sugen, Inc. | Aminoheteroaryl compounds as protein kinase inhibitors |
| WO2004113279A1 (en)* | 2003-06-20 | 2004-12-29 | Glaxo Group Limited | Inhibitors of matrix metalloproteinase |
| US7375248B2 (en) | 2003-06-20 | 2008-05-20 | Glaxo Group Limited | Inhibitors of matrix metalloproteinase |
| US8821869B2 (en) | 2003-08-04 | 2014-09-02 | Amgen Fremont Inc. | Treatment methods using c-Met antibodies |
| US7498420B2 (en) | 2003-08-04 | 2009-03-03 | Amgen Fremont Inc. | Antibodies to c-Met |
| US8163280B2 (en) | 2003-08-04 | 2012-04-24 | Amgen Fremont Inc. | Antibodies to c-Met |
| US8562985B2 (en) | 2003-08-04 | 2013-10-22 | Amgen Fremont Inc. | Antibodies to c-Met |
| WO2005016967A2 (en) | 2003-08-13 | 2005-02-24 | Pfizer Products Inc. | Modified human igf-1r antibodies |
| US7208500B2 (en) | 2003-08-29 | 2007-04-24 | Agouron Pharmaceuticals, Inc. | Thienopyridine-phenylacetamides and their derivatives useful as new anti-angiogenic agents |
| WO2005023759A2 (en) | 2003-09-03 | 2005-03-17 | Array Biopharma Inc. | Heterocyclic inhibitors of mek and methods of use thereof |
| US9718883B2 (en) | 2003-09-10 | 2017-08-01 | Amgen Fremont Inc. | Antibodies to M-CSF |
| US7326414B2 (en) | 2003-09-10 | 2008-02-05 | Warner-Lambert Company Llc | Antibodies to M-CSF |
| US7592430B2 (en) | 2003-09-10 | 2009-09-22 | Amgen Fremont | Antibodies to M-CSF |
| EP3170840A1 (en) | 2003-09-10 | 2017-05-24 | Warner-Lambert Company LLC | Antibodies to m-csf |
| US10280219B2 (en) | 2003-09-10 | 2019-05-07 | Amgen Fremont Inc. | Antibodies to M-CSF |
| EP2251327A2 (en) | 2003-11-19 | 2010-11-17 | Array Biopharma, Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
| WO2005051300A2 (en) | 2003-11-19 | 2005-06-09 | Array Biopharma Inc. | Bicyclic inhibitors of mek and methods of use thereof |
| US7399770B2 (en) | 2004-01-31 | 2008-07-15 | Sanofi-Aventis Deutschland Gmbh | Thieno-imino acid derivatives for use as matrix metalloproteinase inhibitors |
| US7579487B2 (en) | 2004-05-11 | 2009-08-25 | Merck & Co., Inc. | Process for making N-sulfonated-amino acid derivatives |
| US7648992B2 (en) | 2004-07-05 | 2010-01-19 | Astrazeneca Ab | Hydantoin derivatives for the treatment of obstructive airway diseases |
| US7989620B2 (en) | 2004-07-05 | 2011-08-02 | Astrazeneca Ab | Hydantoin derivatives for the treatment of obstructive airway diseases |
| US7618626B2 (en) | 2004-07-16 | 2009-11-17 | Pfizer Inc | Combination treatment for non-hematologic malignancies |
| US7858643B2 (en) | 2004-08-26 | 2010-12-28 | Agouron Pharmaceuticals, Inc. | Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors |
| US8785632B2 (en) | 2004-08-26 | 2014-07-22 | Agouron Pharmaceuticals, Inc. | Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors |
| US7700604B2 (en) | 2004-12-17 | 2010-04-20 | Astrazeneca Ab | Hydantoin derivatives as metalloproteinase inhibitors |
| US7655664B2 (en) | 2004-12-17 | 2010-02-02 | Astrazeneca Ab | Hydantoin derivatives as metalloproteinase inhibitors |
| EP2322551A2 (en) | 2004-12-22 | 2011-05-18 | Amgen, Inc | Compositions comprising Anti-IGF-1R Antibodies and Methods for their Production |
| EP2322550A1 (en) | 2004-12-22 | 2011-05-18 | Amgen, Inc | Compositions comprising anti-IGF-1R Antibodies and Methods for obtaining said Antibodies |
| US7429667B2 (en) | 2005-01-20 | 2008-09-30 | Ardea Biosciences, Inc. | Phenylamino isothiazole carboxamidines as MEK inhibitors |
| US7652047B2 (en) | 2005-01-20 | 2010-01-26 | Ardea Biosciences, Inc. | Phenylamino isothiazole carboxamidines as MEK inhibitors |
| WO2007044084A2 (en) | 2005-05-18 | 2007-04-19 | Array Biopharma Inc. | Heterocyclic inhibitors of mek and methods of use thereof |
| EP2364973A1 (en) | 2005-05-18 | 2011-09-14 | Array Biopharma, Inc. | Heterocyclic inhibitors of MEK and Methods of use thereof |
| EP2361905A1 (en) | 2005-05-18 | 2011-08-31 | Array Biopharma Inc. | Heterocyclic Inhibitors of MEK and methods of use thereof |
| US8829052B2 (en) | 2005-07-21 | 2014-09-09 | Ardea Biosciences, Inc. | Derivatives of N-(arylamino)sulfonamides as inhibitors of MEK |
| US8101799B2 (en) | 2005-07-21 | 2012-01-24 | Ardea Biosciences | Derivatives of N-(arylamino) sulfonamides as inhibitors of MEK |
| US7759518B2 (en) | 2005-07-21 | 2010-07-20 | Ardea Biosciences | Derivatives of N-(arylamino) sulfonamides as inhibitors of MEK |
| EP2372363A1 (en) | 2005-09-20 | 2011-10-05 | OSI Pharmaceuticals, Inc. | Biological markers predictive of anti-cancer response to insulin-like growth factor-1 |
| WO2007035744A1 (en) | 2005-09-20 | 2007-03-29 | Osi Pharmaceuticals, Inc. | Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors |
| WO2007076245A2 (en) | 2005-12-21 | 2007-07-05 | Array Biopharma Inc. | Novel hydrogen sulfate salt |
| US7842836B2 (en) | 2006-04-11 | 2010-11-30 | Ardea Biosciences | N-aryl-N'alkyl sulfamides as MEK inhibitors |
| US7897624B2 (en) | 2006-04-18 | 2011-03-01 | Ardea Biosciences | Pyridone sulfonamides and pyridone sulfamides as MEK inhibitors |
| US8716318B2 (en) | 2006-04-18 | 2014-05-06 | Ardea Biosciences | Pyridone sulfonamides and pyridone sulfamides as MEK inhibitors |
| US8183251B2 (en) | 2006-11-29 | 2012-05-22 | Astrazeneca Ab | Hydantoin compounds and pharmaceutical compositions thereof |
| WO2008075196A1 (en) | 2006-12-15 | 2008-06-26 | Pfizer Products Inc. | Benzimidazole derivatives |
| US7820664B2 (en) | 2007-01-19 | 2010-10-26 | Bayer Schering Pharma Ag | Inhibitors of MEK |
| US8063049B2 (en) | 2007-01-19 | 2011-11-22 | Ardea Biosciences, Inc. | Inhibitors of MEK |
| WO2008129380A1 (en) | 2007-04-18 | 2008-10-30 | Pfizer Products Inc. | Sulfonyl amide derivatives for the treatment of abnormal cell growth |
| US8530463B2 (en) | 2007-05-07 | 2013-09-10 | Hale Biopharma Ventures Llc | Multimodal particulate formulations |
| WO2009018238A1 (en) | 2007-07-30 | 2009-02-05 | Ardea Biosciences, Inc. | Combinations of mek inhibitors and raf kinase inhibitors and uses thereof |
| EP2690101A1 (en) | 2007-12-19 | 2014-01-29 | Genentech, Inc. | 5-Anilinoimidazopyridines and Methods of Use |
| WO2009082687A1 (en) | 2007-12-21 | 2009-07-02 | Genentech, Inc. | Azaindolizines and methods of use |
| US11433065B2 (en) | 2008-01-04 | 2022-09-06 | Intellikine Llc | Certain chemical entities, compositions and methods |
| EP3613743A1 (en) | 2008-01-04 | 2020-02-26 | Intellikine, LLC | Processes for the preparation of 1h-pyrazolo[3,4-d]pyrimidin-4-amine derivatives |
| WO2009114870A2 (en) | 2008-03-14 | 2009-09-17 | Intellikine, Inc. | Kinase inhibitors and methods of use |
| US11793786B2 (en) | 2008-03-28 | 2023-10-24 | Neurelis, Inc. | Administration of benzodiazepine compositions |
| US12268664B1 (en) | 2008-03-28 | 2025-04-08 | Neurelis, Inc. | Administration of benzodiazepine compositions |
| US9763876B2 (en) | 2008-03-28 | 2017-09-19 | Hale Biopharma Ventures, Llc | Administration of benzodiazepine compositions |
| US11241414B2 (en) | 2008-03-28 | 2022-02-08 | Neurelis, Inc. | Administration of benzodiazepine compositions |
| EP3009436A1 (en) | 2008-07-08 | 2016-04-20 | Intellikine, LLC | Kinase inhibitors and methods of use |
| WO2010045495A2 (en) | 2008-10-16 | 2010-04-22 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Fully human antibodies to high molecular weight-melanoma associated antigen and uses thereof |
| WO2010051043A1 (en) | 2008-11-03 | 2010-05-06 | Intellikine, Inc. | Benzoxazole kinase inhibitors and methods of use |
| EP3153023A1 (en) | 2008-11-03 | 2017-04-12 | Intellikine, LLC | Benzoxazole kinase inhibitors and methods of use |
| WO2010091150A1 (en) | 2009-02-05 | 2010-08-12 | Immunogen, Inc. | Novel benzodiazepine derivatives |
| EP3360879A1 (en) | 2009-02-05 | 2018-08-15 | ImmunoGen, Inc. | Benzodiazepine derivatives as cytotoxic agents |
| EP3100745A1 (en) | 2009-02-05 | 2016-12-07 | Immunogen, Inc. | Novel benzodiazepine derivatives |
| WO2010090764A1 (en) | 2009-02-09 | 2010-08-12 | Supergen, Inc. | Pyrrolopyrimidinyl axl kinase inhibitors |
| WO2010099139A2 (en) | 2009-02-25 | 2010-09-02 | Osi Pharmaceuticals, Inc. | Combination anti-cancer therapy |
| WO2010099137A2 (en) | 2009-02-26 | 2010-09-02 | Osi Pharmaceuticals, Inc. | In situ methods for monitoring the emt status of tumor cells in vivo |
| WO2010099138A2 (en) | 2009-02-27 | 2010-09-02 | Osi Pharmaceuticals, Inc. | Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation |
| WO2010099364A2 (en) | 2009-02-27 | 2010-09-02 | Osi Pharmaceuticals, Inc. | Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation |
| WO2010098866A1 (en) | 2009-02-27 | 2010-09-02 | Supergen, Inc. | Cyclopentathiophene/cyclohexathiophene dna methyltransferase inhibitors |
| WO2010099363A1 (en) | 2009-02-27 | 2010-09-02 | Osi Pharmaceuticals, Inc. | Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation |
| WO2010108652A1 (en) | 2009-03-27 | 2010-09-30 | Ardea Biosciences Inc. | Dihydropyridin sulfonamides and dihydropyridin sulfamides as mek inhibitors |
| US8895546B2 (en) | 2009-03-27 | 2014-11-25 | Hale Biopharma Ventures, Llc | Administration of benzodiazepine compositions |
| WO2010129816A2 (en) | 2009-05-07 | 2010-11-11 | Intellikine, Inc. | Heterocyclic compounds and uses thereof |
| EP2918589A1 (en) | 2009-07-15 | 2015-09-16 | Intellikine, LLC | Adenine derivative as pi3k inhibitor |
| EP3441392A1 (en) | 2009-07-15 | 2019-02-13 | Intellikine, LLC | A pharmaceutical composition for oral administration |
| WO2011014726A1 (en) | 2009-07-31 | 2011-02-03 | Osi Pharmaceuticals, Inc. | Mtor inhibitor and angiogenesis inhibitor combination therapy |
| WO2011022439A1 (en) | 2009-08-17 | 2011-02-24 | Intellikine, Inc. | Heterocyclic compounds and uses thereof |
| WO2011027249A2 (en) | 2009-09-01 | 2011-03-10 | Pfizer Inc. | Benzimidazole derivatives |
| US9034861B2 (en) | 2009-10-13 | 2015-05-19 | Allomek Therapeutics Llc | MEK inhibitors useful in the treatment of diseases |
| WO2011049625A1 (en) | 2009-10-20 | 2011-04-28 | Mansour Samadpour | Method for aflatoxin screening of products |
| EP3050876A2 (en) | 2009-11-05 | 2016-08-03 | Rhizen Pharmaceuticals S.A. | Kinase modulators |
| EP3444242A2 (en) | 2009-11-05 | 2019-02-20 | Rhizen Pharmaceuticals S.A. | Novel benzopyran kinase modulators |
| WO2011100403A1 (en) | 2010-02-10 | 2011-08-18 | Immunogen, Inc | Cd20 antibodies and uses thereof |
| EP3597651A1 (en) | 2010-02-12 | 2020-01-22 | Pfizer Inc | Salts and polymorphs of 8-fluoro-2-{4- [(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6h-azepino[5,4,3- cd]indol-6-one |
| WO2011098971A1 (en) | 2010-02-12 | 2011-08-18 | Pfizer Inc. | Salts and polymorphs of 8-fluoro-2-{4-[(methylamino}methyl]phenyl}-1,3,4,5-tetrahydro-6h-azepino[5,4,3-cd]indol-6-one |
| EP4166558A1 (en) | 2010-02-12 | 2023-04-19 | Pfizer Inc. | Salts and polymorphs of 8-fluoro-2-{4- [(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6h-azepino[5,4,3- cd]indol-6-one |
| EP3150610A1 (en) | 2010-02-12 | 2017-04-05 | Pfizer Inc | Salts and polymorphs of 8-fluoro-2-{4-[(methylamino}methyl]phenyl}-1,3,4,5-tetrahydro-6h-azepino[5,4,3-cd]indol-6-one |
| WO2011109584A2 (en) | 2010-03-03 | 2011-09-09 | OSI Pharmaceuticals, LLC | Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors |
| WO2011109572A2 (en) | 2010-03-03 | 2011-09-09 | OSI Pharmaceuticals, LLC | Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors |
| EP3450432A1 (en) | 2010-05-17 | 2019-03-06 | Incozen Therapeutics Pvt. Ltd. | Novel 3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued - 3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of protein kinases |
| WO2011145035A1 (en) | 2010-05-17 | 2011-11-24 | Indian Incozen Therapeutics Pvt. Ltd. | Novel 3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued -3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of protein kinases |
| WO2011146882A1 (en) | 2010-05-21 | 2011-11-24 | Intellikine, Inc. | Chemical compounds, compositions and methods for kinase modulation |
| EP3135692A1 (en) | 2010-06-16 | 2017-03-01 | University of Pittsburgh of the Commonwealth System of Higher Education | Antibodies to endoplasmin and their use |
| WO2012052948A1 (en) | 2010-10-20 | 2012-04-26 | Pfizer Inc. | Pyridine- 2- derivatives as smoothened receptor modulators |
| WO2012064973A2 (en) | 2010-11-10 | 2012-05-18 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| US9840505B2 (en) | 2011-01-10 | 2017-12-12 | Infinity Pharmaceuticals, Inc. | Solid forms of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1 (2H)-one and methods of use thereof |
| USRE46621E1 (en) | 2011-01-10 | 2017-12-05 | Infinity Pharmaceuticals, Inc. | Processes for preparing isoquinolinones and solid forms of isoquinolinones |
| US9290497B2 (en) | 2011-01-10 | 2016-03-22 | Infinity Pharmaceuticals, Inc. | Processes for preparing isoquinolinones and solid forms of isoquinolinones |
| US10550122B2 (en) | 2011-01-10 | 2020-02-04 | Infinity Pharmaceuticals, Inc. | Solid forms of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one and methods of use thereof |
| WO2012097000A1 (en) | 2011-01-10 | 2012-07-19 | Pingda Ren | Processes for preparing isoquinolinones and solid forms of isoquinolinones |
| EP3238722A1 (en) | 2011-01-10 | 2017-11-01 | Infinity Pharmaceuticals, Inc. | Solid forms of isoquinolinones |
| US11312718B2 (en) | 2011-01-10 | 2022-04-26 | Infinity Pharmaceuticals, Inc. | Formulations of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one |
| EP3581574A1 (en) | 2011-01-10 | 2019-12-18 | Infinity Pharmaceuticals, Inc. | A composition for oral administration for use in the treatment of cancer, an inflammatory disease or an auto-immune disease |
| WO2012106556A2 (en) | 2011-02-02 | 2012-08-09 | Amgen Inc. | Methods and compositons relating to inhibition of igf-1r |
| WO2012128868A1 (en) | 2011-02-15 | 2012-09-27 | Immunogen, Inc. | Cytotoxic benzodiazepine derivatives |
| EP3053600A1 (en) | 2011-02-15 | 2016-08-10 | ImmunoGen, Inc. | Cytotoxic benzodiazepine derivatives |
| WO2012112708A1 (en) | 2011-02-15 | 2012-08-23 | Immunogen, Inc. | Cytotoxic benzodiazepine derivatives and methods of preparation |
| EP3666289A1 (en) | 2011-02-15 | 2020-06-17 | ImmunoGen, Inc. | Cytotoxic benzodiazepine derivatives |
| WO2012116040A1 (en) | 2011-02-22 | 2012-08-30 | OSI Pharmaceuticals, LLC | Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors in hepatocellular carcinoma |
| US9127000B2 (en) | 2011-02-23 | 2015-09-08 | Intellikine, LLC. | Heterocyclic compounds and uses thereof |
| WO2012116237A2 (en) | 2011-02-23 | 2012-08-30 | Intellikine, Llc | Heterocyclic compounds and uses thereof |
| WO2012142164A1 (en) | 2011-04-12 | 2012-10-18 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Human monoclonal antibodies that bind insulin-like growth factor (igf) i and ii |
| WO2012145183A2 (en) | 2011-04-19 | 2012-10-26 | Pfizer Inc. | Combinations of anti-4-1bb antibodies and adcc-inducing antibodies for the treatment of cancer |
| EP3536708A1 (en) | 2011-04-19 | 2019-09-11 | Pfizer Inc | Combinations of anti-4-1bb antibodies and adcc-inducing antibodies for the treatment of cancer |
| WO2012149014A1 (en) | 2011-04-25 | 2012-11-01 | OSI Pharmaceuticals, LLC | Use of emt gene signatures in cancer drug discovery, diagnostics, and treatment |
| WO2012151525A1 (en) | 2011-05-04 | 2012-11-08 | Rhizen Pharmaceuticals Sa | Novel compounds as modulators of protein kinases |
| US12324852B2 (en) | 2011-06-14 | 2025-06-10 | Neurelis, Inc. | Administration of benzodiazepine compositions |
| US12337061B2 (en) | 2011-06-14 | 2025-06-24 | Neurelis, Inc. | Administration of benzodiazepine compositions |
| WO2013012918A1 (en) | 2011-07-19 | 2013-01-24 | Infinity Pharmaceuticals Inc. | Heterocyclic compounds and uses thereof |
| WO2013012915A1 (en) | 2011-07-19 | 2013-01-24 | Infinity Pharmaceuticals Inc. | Heterocyclic compounds and uses thereof |
| EP3409278A1 (en) | 2011-07-21 | 2018-12-05 | Tolero Pharmaceuticals, Inc. | Heterocyclic protein kinase inhibitors |
| EP3812387A1 (en) | 2011-07-21 | 2021-04-28 | Sumitomo Dainippon Pharma Oncology, Inc. | Heterocyclic protein kinase inhibitors |
| US10875864B2 (en) | 2011-07-21 | 2020-12-29 | Sumitomo Dainippon Pharma Oncology, Inc. | Substituted imidazo[1,2-B]pyridazines as protein kinase inhibitors |
| WO2013032591A1 (en) | 2011-08-29 | 2013-03-07 | Infinity Pharmaceuticals Inc. | Heterocyclic compounds and uses thereof |
| WO2013042006A1 (en) | 2011-09-22 | 2013-03-28 | Pfizer Inc. | Pyrrolopyrimidine and purine derivatives |
| US9630979B2 (en) | 2011-09-29 | 2017-04-25 | Infinity Pharmaceuticals, Inc. | Inhibitors of monoacylglycerol lipase and methods of their use |
| WO2013049332A1 (en) | 2011-09-29 | 2013-04-04 | Infinity Pharmaceuticals, Inc. | Inhibitors of monoacylglycerol lipase and methods of their use |
| EP3275902A1 (en) | 2011-10-04 | 2018-01-31 | IGEM Therapeutics Limited | Ige anti-hmw-maa antibody |
| WO2013050725A1 (en) | 2011-10-04 | 2013-04-11 | King's College London | Ige anti -hmw-maa antibody |
| WO2013068902A1 (en) | 2011-11-08 | 2013-05-16 | Pfizer Inc. | Methods of treating inflammatory disorders using anti-m-csf antibodies |
| US10259846B2 (en) | 2012-02-22 | 2019-04-16 | The Regents Of The University Of Colorado | Bouvardin derivatives and therapeutic uses thereof |
| US9452215B2 (en) | 2012-02-22 | 2016-09-27 | The Regents Of The University Of Colorado | Bourvadin derivatives and therapeutic uses thereof |
| EP3345624A1 (en) | 2012-02-22 | 2018-07-11 | The Regents Of The University Of Colorado | Bouvardin derivatives and therapeutic uses thereof |
| WO2013126617A1 (en) | 2012-02-22 | 2013-08-29 | The Regents Of The University Of Colorado, A Body Corporate | Bouvardin derivatives and therapeutic uses thereof |
| WO2013144737A2 (en) | 2012-03-30 | 2013-10-03 | Rhizen Pharmaceuticals Sa | Novel 3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued -3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of c-met protein kinases |
| WO2013152252A1 (en) | 2012-04-06 | 2013-10-10 | OSI Pharmaceuticals, LLC | Combination anti-cancer therapy |
| WO2013154878A1 (en) | 2012-04-10 | 2013-10-17 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| EP3505534A1 (en) | 2012-06-08 | 2019-07-03 | Sutro Biopharma, Inc. | Antibodies comprising sitespecific nonnatural amino acid residues, methods of their preparation and methods of their use |
| WO2013185115A1 (en) | 2012-06-08 | 2013-12-12 | Sutro Biopharma, Inc. | Antibodies comprising site-specific non-natural amino acid residues, methods of their preparation and methods of their use |
| EP3135690A1 (en) | 2012-06-26 | 2017-03-01 | Sutro Biopharma, Inc. | Modified fc proteins comprising site-specific non-natural amino acid residues, conjugates of the same, methods of their preparation and methods of their use |
| WO2014031566A1 (en) | 2012-08-22 | 2014-02-27 | Immunogen, Inc. | Cytotoxic benzodiazepine derivatives |
| WO2014036492A1 (en) | 2012-08-31 | 2014-03-06 | Sutro Biopharma, Inc. | Modified amino acids comprising an azido group |
| EP4074728A1 (en) | 2012-08-31 | 2022-10-19 | Sutro Biopharma, Inc. | Modified peptides comprising an azido group |
| EP3584255A1 (en) | 2012-08-31 | 2019-12-25 | Sutro Biopharma, Inc. | Modified amino acids comprising an azido group |
| US10766865B2 (en) | 2012-10-16 | 2020-09-08 | Sumitomo Dainippon Pharma Oncology, Inc. | PKM2 modulators and methods for their use |
| WO2014071109A1 (en) | 2012-11-01 | 2014-05-08 | Infinity Pharmaceuticals, Inc. | Treatment of cancers using pi3 kinase isoform modulators |
| WO2014134486A2 (en) | 2013-02-28 | 2014-09-04 | Immunogen, Inc. | Conjugates comprising cell-binding agents and cytotoxic agents |
| EP3566750A2 (en) | 2013-02-28 | 2019-11-13 | ImmunoGen, Inc. | Conjugates comprising cell-binding agents and cytotoxic agents |
| WO2014134483A2 (en) | 2013-02-28 | 2014-09-04 | Immunogen, Inc. | Conjugates comprising cell-binding agents and cytotoxic agents |
| US10752594B2 (en) | 2013-03-14 | 2020-08-25 | Sumitomo Dainippon Pharma Oncology, Inc. | JAK1 and ALK2 inhibitors and methods for their use |
| EP3590932A1 (en) | 2013-03-14 | 2020-01-08 | Tolero Pharmaceuticals, Inc. | Jak2 and alk2 inhibitors and methods for their use |
| US10919850B2 (en) | 2013-03-15 | 2021-02-16 | Araxes Pharma Llc | Covalent inhibitors of KRas G12C |
| US9227978B2 (en) | 2013-03-15 | 2016-01-05 | Araxes Pharma Llc | Covalent inhibitors of Kras G12C |
| WO2014152588A1 (en) | 2013-03-15 | 2014-09-25 | Araxes Pharma Llc | Covalent inhibitors of kras g12c |
| USRE50527E1 (en) | 2013-03-15 | 2025-08-12 | Araxes Pharma Llc | Covalent inhibitors of KRAS G12C |
| WO2014151386A1 (en) | 2013-03-15 | 2014-09-25 | Infinity Pharmaceuticals, Inc. | Salts and solid forms of isoquinolinones and composition comprising and methods of using the same |
| US9745319B2 (en) | 2013-03-15 | 2017-08-29 | Araxes Pharma Llc | Irreversible covalent inhibitors of the GTPase K-Ras G12C |
| WO2014151147A1 (en) | 2013-03-15 | 2014-09-25 | Intellikine, Llc | Combination of kinase inhibitors and uses thereof |
| US10273207B2 (en) | 2013-03-15 | 2019-04-30 | Araxes Pharma Llc | Covalent inhibitors of kras G12C |
| WO2014143659A1 (en) | 2013-03-15 | 2014-09-18 | Araxes Pharma Llc | Irreversible covalent inhibitors of the gtpase k-ras g12c |
| EP3401314A1 (en) | 2013-03-15 | 2018-11-14 | Araxes Pharma LLC | Covalent inhibitors of kras g12c |
| US9926267B2 (en) | 2013-03-15 | 2018-03-27 | Araxes Pharma Llc | Covalent inhibitors of K-Ras G12C |
| WO2014194254A1 (en) | 2013-05-30 | 2014-12-04 | Infinity Pharmaceuticals, Inc. | Treatment of cancers using pi3 kinase isoform modulators |
| EP3811974A1 (en) | 2013-05-30 | 2021-04-28 | Infinity Pharmaceuticals, Inc. | Treatment of cancers using pi3 kinase isoform modulators |
| WO2014194030A2 (en) | 2013-05-31 | 2014-12-04 | Immunogen, Inc. | Conjugates comprising cell-binding agents and cytotoxic agents |
| EP3336103A1 (en) | 2013-07-10 | 2018-06-20 | Sutro Biopharma, Inc. | Antibodies comprising multiple site-specific non-natural amino acid residues, methods of their preparation and methods of their use |
| WO2015006555A2 (en) | 2013-07-10 | 2015-01-15 | Sutro Biopharma, Inc. | Antibodies comprising multiple site-specific non-natural amino acid residues, methods of their preparation and methods of their use |
| WO2015051341A1 (en) | 2013-10-03 | 2015-04-09 | Araxes Pharma Llc | Inhibitors of erk and methods of use |
| WO2015051244A1 (en) | 2013-10-04 | 2015-04-09 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| EP3964507A1 (en) | 2013-10-04 | 2022-03-09 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| WO2015051241A1 (en) | 2013-10-04 | 2015-04-09 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| EP3636639A1 (en) | 2013-10-10 | 2020-04-15 | Araxes Pharma LLC | Inhibitors of kras g12c |
| US11878985B2 (en) | 2013-10-10 | 2024-01-23 | Araxes Pharma Llc | Substituted quinazolines as inhibitors of KRAS G12C |
| US10927125B2 (en) | 2013-10-10 | 2021-02-23 | Araxes Pharma Llc | Substituted cinnolines as inhibitors of KRAS G12C |
| US10370386B2 (en) | 2013-10-10 | 2019-08-06 | Araxes Pharma Llc | Substituted quinolines as inhibitors of KRAS G12C |
| US12234244B2 (en) | 2013-10-10 | 2025-02-25 | Araxes Pharma Llc | Substituted piperazines as inhibitors of KRAS G12C |
| WO2015054572A1 (en) | 2013-10-10 | 2015-04-16 | Araxes Pharma Llc | Inhibitors of kras g12c |
| US9840516B2 (en) | 2013-10-10 | 2017-12-12 | Araxes Pharma Llc | Substituted quinazolines as inhibitors of KRAS G12C |
| WO2015054658A1 (en) | 2013-10-11 | 2015-04-16 | Sutro Biopharma, Inc. | Modified amino acids comprising tetrazine functional groups, methods of preparation, and methods of their use |
| WO2015061204A1 (en) | 2013-10-21 | 2015-04-30 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| WO2015075598A1 (en) | 2013-11-21 | 2015-05-28 | Pfizer Inc. | 2,6-substituted purine derivatives and their use in the treatment of proliferative disorders |
| WO2015155624A1 (en) | 2014-04-10 | 2015-10-15 | Pfizer Inc. | Dihydropyrrolopyrimidine derivatives |
| WO2015168079A1 (en) | 2014-04-29 | 2015-11-05 | Infinity Pharmaceuticals, Inc. | Pyrimidine or pyridine derivatives useful as pi3k inhibitors |
| WO2015166373A1 (en) | 2014-04-30 | 2015-11-05 | Pfizer Inc. | Cycloalkyl-linked diheterocycle derivatives |
| EP3556757A1 (en) | 2014-04-30 | 2019-10-23 | Pfizer Inc | Cycloalkyl-linked diheterocycle derivatives |
| EP3409669A1 (en) | 2014-06-19 | 2018-12-05 | ARIAD Pharmaceuticals, Inc. | Heteroaryl compounds for kinase inhibition |
| EP3778584A1 (en) | 2014-06-19 | 2021-02-17 | ARIAD Pharmaceuticals, Inc. | Production process of 2-chloro-4-heteroaryl-pyrimidine derivatives |
| WO2016001789A1 (en) | 2014-06-30 | 2016-01-07 | Pfizer Inc. | Pyrimidine derivatives as pi3k inhibitors for use in the treatment of cancer |
| WO2016019280A1 (en) | 2014-07-31 | 2016-02-04 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Human monoclonal antibodies against epha4 and their use |
| US12037404B2 (en) | 2014-07-31 | 2024-07-16 | The Hong Kong University Of Science And Technology | Human monoclonal antibodies against EphA4 and their use |
| EP3473271A1 (en) | 2014-07-31 | 2019-04-24 | The Government of the United States of America as represented by the Secretary of the Department of Health and Human Services | Human monoclonal antibodies against epha4 and their use |
| US10111874B2 (en) | 2014-09-18 | 2018-10-30 | Araxes Pharma Llc | Combination therapies for treatment of cancer |
| US10011600B2 (en) | 2014-09-25 | 2018-07-03 | Araxes Pharma Llc | Methods and compositions for inhibition of Ras |
| US9862701B2 (en) | 2014-09-25 | 2018-01-09 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
| WO2016097918A1 (en) | 2014-12-18 | 2016-06-23 | Pfizer Inc. | Pyrimidine and triazine derivatives and their use as axl inhibitors |
| USRE50490E1 (en) | 2015-04-10 | 2025-07-15 | Araxes Pharma Llc | Substituted quinazoline compounds and methods of use thereof |
| US10829458B2 (en) | 2015-04-10 | 2020-11-10 | Araxes Pharma Llc | Substituted quinazoline compounds and methods of use thereof |
| US10246424B2 (en) | 2015-04-10 | 2019-04-02 | Araxes Pharma Llc | Substituted quinazoline compounds and methods of use thereof |
| US10428064B2 (en) | 2015-04-15 | 2019-10-01 | Araxes Pharma Llc | Fused-tricyclic inhibitors of KRAS and methods of use thereof |
| WO2016178876A2 (en) | 2015-05-01 | 2016-11-10 | Cocrystal Pharma, Inc. | Nucleoside analogs for treatment of the flaviviridae family of viruses and cancer |
| US12338261B2 (en) | 2015-05-18 | 2025-06-24 | Sumitomo Pharma Oncology, Inc. | Alvocidib prodrugs having increased bioavailability |
| EP4006030A2 (en) | 2015-06-04 | 2022-06-01 | Kura Oncology, Inc. | Methods and compositions for inhibiting the interaction of menin with mll proteins |
| WO2017009751A1 (en) | 2015-07-15 | 2017-01-19 | Pfizer Inc. | Pyrimidine derivatives |
| US10144724B2 (en) | 2015-07-22 | 2018-12-04 | Araxes Pharma Llc | Substituted quinazoline compounds and methods of use thereof |
| US10351550B2 (en) | 2015-07-22 | 2019-07-16 | Araxes Pharma Llc | Substituted quinazoline compounds and methods of use thereof |
| US10835537B2 (en) | 2015-08-03 | 2020-11-17 | Sumitomo Dainippon Pharma Oncology, Inc. | Combination therapies for treatment of cancer |
| EP4585268A2 (en) | 2015-09-14 | 2025-07-16 | Twelve Therapeutics, Inc. | Solid forms of isoquinolinone derivatives, process of making, compositions comprising, and methods of using the same |
| US10689356B2 (en) | 2015-09-28 | 2020-06-23 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
| US10647703B2 (en) | 2015-09-28 | 2020-05-12 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
| WO2017058792A1 (en) | 2015-09-28 | 2017-04-06 | Araxes Pharma Llc | Inhibitors of kras g12c mutant proteins |
| WO2017058768A1 (en) | 2015-09-28 | 2017-04-06 | Araxes Pharma Llc | Inhibitors of kras g12c mutant proteins |
| US10975071B2 (en) | 2015-09-28 | 2021-04-13 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
| US10882847B2 (en) | 2015-09-28 | 2021-01-05 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
| US10730867B2 (en) | 2015-09-28 | 2020-08-04 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
| US10858343B2 (en) | 2015-09-28 | 2020-12-08 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
| US10875842B2 (en) | 2015-09-28 | 2020-12-29 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
| US9810690B2 (en) | 2015-10-19 | 2017-11-07 | Araxes Pharma Llc | Method for screening inhibitors of Ras |
| US10414757B2 (en) | 2015-11-16 | 2019-09-17 | Araxes Pharma Llc | 2-substituted quinazoline compounds comprising a substituted heterocyclic group and methods of use thereof |
| WO2017087528A1 (en) | 2015-11-16 | 2017-05-26 | Araxes Pharma Llc | 2-substituted quinazoline compounds comprising a substituted heterocyclic group and methods of use thereof |
| US11021470B2 (en) | 2015-11-16 | 2021-06-01 | Araxes Pharma Llc | 2-substituted quinazoline compounds comprising a substituted heterocyclic group and methods of use thereof |
| WO2017096165A1 (en) | 2015-12-03 | 2017-06-08 | Agios Pharmaceuticals, Inc. | Mat2a inhibitors for treating mtap null cancer |
| US9988357B2 (en) | 2015-12-09 | 2018-06-05 | Araxes Pharma Llc | Methods for preparation of quinazoline derivatives |
| WO2017132617A1 (en) | 2016-01-27 | 2017-08-03 | Sutro Biopharma, Inc. | Anti-cd74 antibody conjugates, compositions comprising anti-cd74 antibody conjugates and methods of using anti-cd74 antibody conjugates |
| WO2017132615A1 (en) | 2016-01-27 | 2017-08-03 | Sutro Biopharma, Inc. | Anti-cd74 antibody conjugates, compositions comprising anti-cd74 antibody conjugates and methods of using anti-cd74 antibody conjugates |
| WO2017161028A1 (en) | 2016-03-16 | 2017-09-21 | Kura Oncology, Inc. | Substituted inhibitors of menin-mll and methods of use |
| US11673898B2 (en) | 2016-03-16 | 2023-06-13 | Kura Oncology, Inc. | Substituted inhibitors of menin-MLL and methods of use |
| US11555041B2 (en) | 2016-03-16 | 2023-01-17 | Kura Oncology, Inc. | Bridged bicyclic inhibitors of menin-MLL and methods of use |
| WO2017161002A1 (en) | 2016-03-16 | 2017-09-21 | Kura Oncology, Inc. | Bridged bicyclic inhibitors of menin-mll and methods of use |
| US10781218B2 (en) | 2016-03-16 | 2020-09-22 | Kura Oncology, Inc. | Substituted inhibitors of menin-MLL and methods of use |
| US10752639B2 (en) | 2016-03-16 | 2020-08-25 | Kura Oncology, Inc. | Bridged bicyclic inhibitors of menin-MLL and methods of use |
| EP4219449A2 (en) | 2016-03-16 | 2023-08-02 | Kura Oncology, Inc. | Substituted indole derivatives and methods of preparation thereof |
| US10822312B2 (en) | 2016-03-30 | 2020-11-03 | Araxes Pharma Llc | Substituted quinazoline compounds and methods of use |
| WO2017197240A1 (en) | 2016-05-12 | 2017-11-16 | The Regents Of The University Of Michigan | Ash1l inhibitors and methods of treatment therewith |
| US11883381B2 (en) | 2016-05-12 | 2024-01-30 | The Regents Of The University Of Michigan | ASH1L inhibitors and methods of treatment therewith |
| US12435379B2 (en) | 2016-05-18 | 2025-10-07 | The University Of Chicago | BTK mutation and ibrutinib resistance |
| US11118233B2 (en) | 2016-05-18 | 2021-09-14 | The University Of Chicago | BTK mutation and ibrutinib resistance |
| WO2017214269A1 (en) | 2016-06-08 | 2017-12-14 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| US10646488B2 (en) | 2016-07-13 | 2020-05-12 | Araxes Pharma Llc | Conjugates of cereblon binding compounds and G12C mutant KRAS, HRAS or NRAS protein modulating compounds and methods of use thereof |
| US10870694B2 (en) | 2016-09-02 | 2020-12-22 | Dana Farber Cancer Institute, Inc. | Composition and methods of treating B cell disorders |
| WO2018045379A1 (en) | 2016-09-02 | 2018-03-08 | Dana-Farber Cancer Institute, Inc. | Composition and methods of treating b cell disorders |
| WO2018064510A1 (en) | 2016-09-29 | 2018-04-05 | Araxes Pharma Llc | Inhibitors of kras g12c mutant proteins |
| US10723738B2 (en) | 2016-09-29 | 2020-07-28 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
| US10280172B2 (en) | 2016-09-29 | 2019-05-07 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
| US10377743B2 (en) | 2016-10-07 | 2019-08-13 | Araxes Pharma Llc | Inhibitors of RAS and methods of use thereof |
| WO2018068017A1 (en) | 2016-10-07 | 2018-04-12 | Araxes Pharma Llc | Heterocyclic compounds as inhibitors of ras and methods of use thereof |
| US11279694B2 (en) | 2016-11-18 | 2022-03-22 | Sumitomo Dainippon Pharma Oncology, Inc. | Alvocidib prodrugs and their use as protein kinase inhibitors |
| WO2018098352A2 (en) | 2016-11-22 | 2018-05-31 | Jun Oishi | Targeting kras induced immune checkpoint expression |
| US10532042B2 (en) | 2016-12-22 | 2020-01-14 | Amgen Inc. | KRAS G12C inhibitors and methods of using the same |
| US11285135B2 (en) | 2016-12-22 | 2022-03-29 | Amgen Inc. | KRAS G12C inhibitors and methods of using the same |
| EP4001269A1 (en) | 2016-12-22 | 2022-05-25 | Amgen Inc. | Benzoisothiazole, isothiazolo[3,4-b]pyridine, quinazoline, phthalazine, pyrido[2,3-d]pyridazine and pyrido[2,3-d]pyrimidine derivatives as kras g12c inhibitors for treating lung, pancreatic or colorectal cancer |
| WO2018119183A2 (en) | 2016-12-22 | 2018-06-28 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
| US11267885B2 (en) | 2017-01-26 | 2022-03-08 | Zlip Holding Limited | CD47 antigen binding unit and uses thereof |
| US11358959B2 (en) | 2017-01-26 | 2022-06-14 | Araxes Pharma Llc | Benzothiophene and benzothiazole compounds and methods of use thereof |
| US11136308B2 (en) | 2017-01-26 | 2021-10-05 | Araxes Pharma Llc | Substituted quinazoline and quinazolinone compounds and methods of use thereof |
| WO2018140600A1 (en) | 2017-01-26 | 2018-08-02 | Araxes Pharma Llc | Fused hetero-hetero bicyclic compounds and methods of use thereof |
| WO2018140598A1 (en) | 2017-01-26 | 2018-08-02 | Araxes Pharma Llc | Fused n-heterocyclic compounds and methods of use thereof |
| WO2018140512A1 (en) | 2017-01-26 | 2018-08-02 | Araxes Pharma Llc | Fused bicyclic benzoheteroaromatic compounds and methods of use thereof |
| WO2018140599A1 (en) | 2017-01-26 | 2018-08-02 | Araxes Pharma Llc | Benzothiophene and benzothiazole compounds and methods of use thereof |
| WO2018140513A1 (en) | 2017-01-26 | 2018-08-02 | Araxes Pharma Llc | 1-(3-(6-(3-hydroxynaphthalen-1-yl)benzofuran-2-yl)azetidin-1yl)prop-2-en-1-one derivatives and similar compounds as kras g12c modulators for treating cancer |
| US11059819B2 (en) | 2017-01-26 | 2021-07-13 | Janssen Biotech, Inc. | Fused hetero-hetero bicyclic compounds and methods of use thereof |
| WO2018140514A1 (en) | 2017-01-26 | 2018-08-02 | Araxes Pharma Llc | 1-(6-(3-hydroxynaphthalen-1-yl)quinazolin-2-yl)azetidin-1-yl)prop-2-en-1-one derivatives and similar compounds as kras g12c inhibitors for the treatment of cancer |
| US11279689B2 (en) | 2017-01-26 | 2022-03-22 | Araxes Pharma Llc | 1-(3-(6-(3-hydroxynaphthalen-1-yl)benzofuran-2-yl)azetidin-1 yl)prop-2-en-1-one derivatives and similar compounds as KRAS G12C modulators for treating cancer |
| US11274093B2 (en) | 2017-01-26 | 2022-03-15 | Araxes Pharma Llc | Fused bicyclic benzoheteroaromatic compounds and methods of use thereof |
| US11944627B2 (en) | 2017-03-24 | 2024-04-02 | Kura Oncology, Inc. | Methods for treating hematological malignancies and Ewing's sarcoma |
| WO2018175746A1 (en) | 2017-03-24 | 2018-09-27 | Kura Oncology, Inc. | Methods for treating hematological malignancies and ewing's sarcoma |
| EP3974429A1 (en) | 2017-05-22 | 2022-03-30 | Amgen Inc. | Precursors of kras g12c inhibitors |
| WO2018217651A1 (en) | 2017-05-22 | 2018-11-29 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
| US11905281B2 (en) | 2017-05-22 | 2024-02-20 | Amgen Inc. | KRAS G12C inhibitors and methods of using the same |
| US10519146B2 (en) | 2017-05-22 | 2019-12-31 | Amgen Inc. | KRAS G12C inhibitors and methods of using the same |
| US11639346B2 (en) | 2017-05-25 | 2023-05-02 | Araxes Pharma Llc | Quinazoline derivatives as modulators of mutant KRAS, HRAS or NRAS |
| US11377441B2 (en) | 2017-05-25 | 2022-07-05 | Araxes Pharma Llc | Covalent inhibitors of KRAS |
| US10745385B2 (en) | 2017-05-25 | 2020-08-18 | Araxes Pharma Llc | Covalent inhibitors of KRAS |
| WO2018218070A2 (en) | 2017-05-25 | 2018-11-29 | Araxes Pharma Llc | Covalent inhibitors of kras |
| WO2018218071A1 (en) | 2017-05-25 | 2018-11-29 | Araxes Pharma Llc | Compounds and methods of use thereof for treatment of cancer |
| WO2018218069A1 (en) | 2017-05-25 | 2018-11-29 | Araxes Pharma Llc | Quinazoline derivatives as modulators of mutant kras, hras or nras |
| US10736897B2 (en) | 2017-05-25 | 2020-08-11 | Araxes Pharma Llc | Compounds and methods of use thereof for treatment of cancer |
| US11542248B2 (en) | 2017-06-08 | 2023-01-03 | Kura Oncology, Inc. | Methods and compositions for inhibiting the interaction of menin with MLL proteins |
| WO2019023316A1 (en) | 2017-07-26 | 2019-01-31 | Sutro Biopharma, Inc. | Methods of using anti-cd74 antibodies and antibody conjugates in treatment of t-cell lymphoma |
| US11993597B2 (en) | 2017-09-08 | 2024-05-28 | Amgen Inc. | Inhibitors of KRAS G12C and methods of using the same |
| EP4403175A2 (en) | 2017-09-08 | 2024-07-24 | Amgen Inc. | Inhibitors of kras g12c and methods of using the same |
| WO2019051291A1 (en) | 2017-09-08 | 2019-03-14 | Amgen Inc. | KRAS G12C INHIBITORS AND METHODS OF USE |
| EP4141005A1 (en) | 2017-09-08 | 2023-03-01 | Amgen Inc. | Inhibitors of kras g12c and methods of using the same |
| US10640504B2 (en) | 2017-09-08 | 2020-05-05 | Amgen Inc. | Inhibitors of KRAS G12C and methods of using the same |
| US11306087B2 (en) | 2017-09-08 | 2022-04-19 | Amgen Inc. | Inhibitors of KRAS G12C and methods of using the same |
| US11497756B2 (en) | 2017-09-12 | 2022-11-15 | Sumitomo Pharma Oncology, Inc. | Treatment regimen for cancers that are insensitive to BCL-2 inhibitors using the MCL-1 inhibitor alvocidib |
| WO2019055909A1 (en) | 2017-09-18 | 2019-03-21 | Sutro Biopharma, Inc. | Anti-folate receptor alpha antibody conjugates and their uses |
| US11649251B2 (en) | 2017-09-20 | 2023-05-16 | Kura Oncology, Inc. | Substituted inhibitors of menin-MLL and methods of use |
| WO2019075367A1 (en) | 2017-10-13 | 2019-04-18 | Tolero Pharmaceuticals, Inc. | Pkm2 activators in combination with reactive oxygen species for treatment of cancer |
| US11833210B2 (en) | 2017-11-10 | 2023-12-05 | The Regents Of The University Of Michigan | ASH1L inhibitors and methods of treatment therewith |
| US11110177B2 (en) | 2017-11-10 | 2021-09-07 | The Regents Of The University Of Michigan | ASH1L degraders and methods of treatment therewith |
| US11786602B2 (en) | 2017-11-10 | 2023-10-17 | The Regents Of The University Of Michigan | ASH1L degraders and methods of treatment therewith |
| US11147885B2 (en) | 2017-11-10 | 2021-10-19 | The Regents Of The University Of Michigan | ASH1L inhibitors and methods of treatment therewith |
| US10632209B2 (en) | 2017-11-10 | 2020-04-28 | The Regents Of The University Of Michigan | ASH1L inhibitors and methods of treatment therewith |
| WO2019094773A1 (en) | 2017-11-10 | 2019-05-16 | The Regents Of The University Of Michigan | Ash1l inhibitors and methods of treatment therewith |
| US12285490B2 (en) | 2017-11-10 | 2025-04-29 | The Regents Of The University Of Michigan | ASH1L degraders and methods of treatment therewith |
| WO2019094772A1 (en) | 2017-11-10 | 2019-05-16 | The Regents Of The University Of Michigan | Ash1l degraders and methods of treatment therewith |
| WO2019113469A1 (en) | 2017-12-07 | 2019-06-13 | The Regents Of The University Of Michigan | Nsd family inhibitors and methods of treatment therewith |
| US11766436B2 (en) | 2018-05-04 | 2023-09-26 | Amgen Inc. | KRAS G12C inhibitors and methods of using the same |
| US11090304B2 (en) | 2018-05-04 | 2021-08-17 | Amgen Inc. | KRAS G12C inhibitors and methods of using the same |
| WO2019213526A1 (en) | 2018-05-04 | 2019-11-07 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
| WO2019213516A1 (en) | 2018-05-04 | 2019-11-07 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
| US11045484B2 (en) | 2018-05-04 | 2021-06-29 | Amgen Inc. | KRAS G12C inhibitors and methods of using the same |
| US10988485B2 (en) | 2018-05-10 | 2021-04-27 | Amgen Inc. | KRAS G12C inhibitors and methods of using the same |
| WO2019217691A1 (en) | 2018-05-10 | 2019-11-14 | Amgen Inc. | Kras g12c inhibitors for the treatment of cancer |
| WO2019232419A1 (en) | 2018-06-01 | 2019-12-05 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
| US11096939B2 (en) | 2018-06-01 | 2021-08-24 | Amgen Inc. | KRAS G12C inhibitors and methods of using the same |
| EP4155293A1 (en) | 2018-06-07 | 2023-03-29 | The Regents of The University of Michigan | Prc1 inhibitors and methods of treatment therewith |
| US11319302B2 (en) | 2018-06-07 | 2022-05-03 | The Regents Of The University Of Michigan | PRC1 inhibitors and methods of treatment therewith |
| WO2019236957A1 (en) | 2018-06-07 | 2019-12-12 | The Regents Of The University Of Michigan | Prc1 inhibitors and methods of treatment therewith |
| WO2019241157A1 (en) | 2018-06-11 | 2019-12-19 | Amgen Inc. | Kras g12c inhibitors for treating cancer |
| EP4268898A2 (en) | 2018-06-11 | 2023-11-01 | Amgen Inc. | Kras g12c inhibitors for treating cancer |
| WO2020050890A2 (en) | 2018-06-12 | 2020-03-12 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
| US11285156B2 (en) | 2018-06-12 | 2022-03-29 | Amgen Inc. | Substituted piperazines as KRAS G12C inhibitors |
| US12083121B2 (en) | 2018-06-12 | 2024-09-10 | Amgen Inc. | Substituted piperazines as KRAS G12C inhibitors |
| US11040038B2 (en) | 2018-07-26 | 2021-06-22 | Sumitomo Dainippon Pharma Oncology, Inc. | Methods for treating diseases associated with abnormal ACVR1 expression and ACVR1 inhibitors for use in the same |
| WO2020028706A1 (en) | 2018-08-01 | 2020-02-06 | Araxes Pharma Llc | Heterocyclic spiro compounds and methods of use thereof for the treatment of cancer |
| US12134620B2 (en) | 2018-08-01 | 2024-11-05 | Araxes Pharma Llc | Heterocyclic spiro compounds and methods of use thereof for the treatment of cancer |
| WO2020060944A1 (en) | 2018-09-17 | 2020-03-26 | Sutro Biopharma, Inc. | Combination therapies with anti-folate receptor antibody conjugates |
| WO2020086739A1 (en) | 2018-10-24 | 2020-04-30 | Araxes Pharma Llc | 2-(2-acryloyl-2,6-diazaspiro[3.4]octan-6-yl)-6-(1h-indazol-4-yl)-benzonitrile derivatives and related compounds as inhibitors of g12c mutant kras protein for inhibiting tumor metastasis |
| WO2020102730A1 (en) | 2018-11-16 | 2020-05-22 | Amgen Inc. | Improved synthesis of key intermediate of kras g12c inhibitor compound |
| US12391691B2 (en) | 2018-11-16 | 2025-08-19 | Amgen Inc. | Synthesis of key intermediate of KRAS G12C inhibitor compound |
| US11299491B2 (en) | 2018-11-16 | 2022-04-12 | Amgen Inc. | Synthesis of key intermediate of KRAS G12C inhibitor compound |
| US12391689B2 (en) | 2018-11-16 | 2025-08-19 | Amgen Inc. | Synthesis of key intermediate of KRAS G12C inhibitor compound |
| EP4234546A2 (en) | 2018-11-16 | 2023-08-30 | Amgen Inc. | Improved synthesis of key intermediate of kras g12c inhibitor compound |
| US12280056B2 (en) | 2018-11-19 | 2025-04-22 | Amgen Inc. | Combination therapy including a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers |
| US11053226B2 (en) | 2018-11-19 | 2021-07-06 | Amgen Inc. | KRAS G12C inhibitors and methods of using the same |
| US11918584B2 (en) | 2018-11-19 | 2024-03-05 | Amgen Inc. | Combination therapy including a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers |
| WO2020106647A2 (en) | 2018-11-19 | 2020-05-28 | Amgen Inc. | Combination therapy including a krasg12c inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers |
| US11439645B2 (en) | 2018-11-19 | 2022-09-13 | Amgen Inc. | Combination therapy including a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers |
| WO2020106640A1 (en) | 2018-11-19 | 2020-05-28 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
| WO2020113071A1 (en) | 2018-11-29 | 2020-06-04 | Araxes Pharma Llc | Compounds and methods of use thereof for treatment of cancer |
| US12077554B2 (en) | 2018-12-04 | 2024-09-03 | Sumitomo Pharma Oncology, Inc. | CDK9 inhibitors and polymorphs thereof for use as agents for treatment of cancer |
| US11034710B2 (en) | 2018-12-04 | 2021-06-15 | Sumitomo Dainippon Pharma Oncology, Inc. | CDK9 inhibitors and polymorphs thereof for use as agents for treatment of cancer |
| US11530231B2 (en) | 2018-12-04 | 2022-12-20 | Sumitomo Pharma Oncology, Inc. | CDK9 inhibitors and polymorphs thereof for use as agents for treatment of cancer |
| US11236069B2 (en) | 2018-12-20 | 2022-02-01 | Amgen Inc. | KIF18A inhibitors |
| WO2020132653A1 (en) | 2018-12-20 | 2020-06-25 | Amgen Inc. | Heteroaryl amides useful as kif18a inhibitors |
| WO2020132649A1 (en) | 2018-12-20 | 2020-06-25 | Amgen Inc. | Heteroaryl amides useful as kif18a inhibitors |
| WO2020132651A1 (en) | 2018-12-20 | 2020-06-25 | Amgen Inc. | Kif18a inhibitors |
| WO2020132648A1 (en) | 2018-12-20 | 2020-06-25 | Amgen Inc. | Kif18a inhibitors |
| US12054476B2 (en) | 2018-12-20 | 2024-08-06 | Amgen Inc. | KIF18A inhibitors |
| US11471456B2 (en) | 2019-02-12 | 2022-10-18 | Sumitomo Pharma Oncology, Inc. | Formulations comprising heterocyclic protein kinase inhibitors |
| WO2020180770A1 (en) | 2019-03-01 | 2020-09-10 | Revolution Medicines, Inc. | Bicyclic heterocyclyl compounds and uses thereof |
| WO2020180768A1 (en) | 2019-03-01 | 2020-09-10 | Revolution Medicines, Inc. | Bicyclic heteroaryl compounds and uses thereof |
| US11793802B2 (en) | 2019-03-20 | 2023-10-24 | Sumitomo Pharma Oncology, Inc. | Treatment of acute myeloid leukemia (AML) with venetoclax failure |
| US11712433B2 (en) | 2019-03-22 | 2023-08-01 | Sumitomo Pharma Oncology, Inc. | Compositions comprising PKM2 modulators and methods of treatment using the same |
| WO2020198077A1 (en) | 2019-03-22 | 2020-10-01 | Sumitomo Dainippon Pharma Oncology, Inc. | Compositions comprising pkm2 modulators and methods of treatment using the same |
| WO2020227105A1 (en) | 2019-05-03 | 2020-11-12 | Sutro Biopharma, Inc. | Anti-bcma antibody conjugates |
| US11426404B2 (en) | 2019-05-14 | 2022-08-30 | Amgen Inc. | Dosing of KRAS inhibitor for treatment of cancers |
| US11236091B2 (en) | 2019-05-21 | 2022-02-01 | Amgen Inc. | Solid state forms |
| US12398133B2 (en) | 2019-05-21 | 2025-08-26 | Amgen Inc. | Solid state forms |
| US11827635B2 (en) | 2019-05-21 | 2023-11-28 | Amgen Inc. | Solid state forms |
| US12415806B1 (en) | 2019-05-21 | 2025-09-16 | Amgen Inc. | Solid state forms |
| US12421234B1 (en) | 2019-05-21 | 2025-09-23 | Amgen Inc. | Solid state forms |
| WO2021003417A1 (en) | 2019-07-03 | 2021-01-07 | Sumitomo Dainippon Pharma Oncology, Inc. | Tyrosine kinase non-receptor 1 (tnk1) inhibitors and uses thereof |
| US11529350B2 (en) | 2019-07-03 | 2022-12-20 | Sumitomo Pharma Oncology, Inc. | Tyrosine kinase non-receptor 1 (TNK1) inhibitors and uses thereof |
| WO2021026098A1 (en) | 2019-08-02 | 2021-02-11 | Amgen Inc. | Kif18a inhibitors |
| WO2021026101A1 (en) | 2019-08-02 | 2021-02-11 | Amgen Inc. | Kif18a inhibitors |
| WO2021026100A1 (en) | 2019-08-02 | 2021-02-11 | Amgen Inc. | Pyridine derivatives as kif18a inhibitors |
| WO2021026099A1 (en) | 2019-08-02 | 2021-02-11 | Amgen Inc. | Kif18a inhibitors |
| WO2021055728A1 (en) | 2019-09-18 | 2021-03-25 | Merck Sharp & Dohme Corp. | Small molecule inhibitors of kras g12c mutant |
| WO2021067215A1 (en) | 2019-09-30 | 2021-04-08 | Agios Pharmaceuticals, Inc. | Piperidine compounds as menin inhibitors |
| WO2021081212A1 (en) | 2019-10-24 | 2021-04-29 | Amgen Inc. | Pyridopyrimidine derivatives useful as kras g12c and kras g12d inhibitors in the treatment of cancer |
| WO2021086833A1 (en) | 2019-10-28 | 2021-05-06 | Merck Sharp & Dohme Corp. | Small molecule inhibitors of kras g12c mutant |
| WO2021085653A1 (en) | 2019-10-31 | 2021-05-06 | Taiho Pharmaceutical Co., Ltd. | 4-aminobut-2-enamide derivatives and salts thereof |
| WO2021091956A1 (en) | 2019-11-04 | 2021-05-14 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2021091967A1 (en) | 2019-11-04 | 2021-05-14 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2021091982A1 (en) | 2019-11-04 | 2021-05-14 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2021092115A1 (en) | 2019-11-08 | 2021-05-14 | Revolution Medicines, Inc. | Bicyclic heteroaryl compounds and uses thereof |
| EP4620531A2 (en) | 2019-11-08 | 2025-09-24 | Revolution Medicines, Inc. | Bicyclic heteroaryl compounds and uses thereof |
| WO2021097212A1 (en) | 2019-11-14 | 2021-05-20 | Amgen Inc. | Improved synthesis of kras g12c inhibitor compound |
| WO2021097207A1 (en) | 2019-11-14 | 2021-05-20 | Amgen Inc. | Improved synthesis of kras g12c inhibitor compound |
| WO2021108683A1 (en) | 2019-11-27 | 2021-06-03 | Revolution Medicines, Inc. | Covalent ras inhibitors and uses thereof |
| WO2021107160A1 (en) | 2019-11-29 | 2021-06-03 | Taiho Pharmaceutical Co., Ltd. | A compound having inhibitory activity against kras g12d mutation |
| WO2021142026A1 (en) | 2020-01-07 | 2021-07-15 | Revolution Medicines, Inc. | Shp2 inhibitor dosing and methods of treating cancer |
| WO2021155006A1 (en) | 2020-01-31 | 2021-08-05 | Les Laboratoires Servier Sas | Inhibitors of cyclin-dependent kinases and uses thereof |
| WO2021178597A1 (en) | 2020-03-03 | 2021-09-10 | Sutro Biopharma, Inc. | Antibodies comprising site-specific glutamine tags, methods of their preparation and methods of their use |
| WO2021204159A1 (en) | 2020-04-08 | 2021-10-14 | Agios Pharmaceuticals, Inc. | Menin inhibitors and methods of use for treating cancer |
| WO2021207310A1 (en) | 2020-04-08 | 2021-10-14 | Agios Pharmaceuticals, Inc. | Menin inhibitors and methods of use for treating cancer |
| WO2021215545A1 (en) | 2020-04-24 | 2021-10-28 | Taiho Pharmaceutical Co., Ltd. | Anticancer combination therapy with n-(1-acryloyl-azetidin-3-yl)-2-((1h-indazol-3-yl)amino)methyl)-1h-imidazole-5-carboxamide inhibitor of kras-g12c |
| WO2021215544A1 (en) | 2020-04-24 | 2021-10-28 | Taiho Pharmaceutical Co., Ltd. | Kras g12d protein inhibitors |
| WO2021257736A1 (en) | 2020-06-18 | 2021-12-23 | Revolution Medicines, Inc. | Methods for delaying, preventing, and treating acquired resistance to ras inhibitors |
| US11858925B2 (en) | 2020-07-10 | 2024-01-02 | The Regents Of The University Of Michigan | GAS41 inhibitors and methods of use thereof |
| WO2022014640A1 (en) | 2020-07-15 | 2022-01-20 | 大鵬薬品工業株式会社 | Pyrimidine compound-containing combination to be used in tumor treatment |
| WO2022060583A1 (en) | 2020-09-03 | 2022-03-24 | Revolution Medicines, Inc. | Use of sos1 inhibitors to treat malignancies with shp2 mutations |
| WO2022060836A1 (en) | 2020-09-15 | 2022-03-24 | Revolution Medicines, Inc. | Indole derivatives as ras inhibitors in the treatment of cancer |
| US11746103B2 (en) | 2020-12-10 | 2023-09-05 | Sumitomo Pharma Oncology, Inc. | ALK-5 inhibitors and uses thereof |
| WO2022140427A1 (en) | 2020-12-22 | 2022-06-30 | Qilu Regor Therapeutics Inc. | Sos1 inhibitors and uses thereof |
| WO2022221227A1 (en) | 2021-04-13 | 2022-10-20 | Nuvalent, Inc. | Amino-substituted heterocycles for treating cancers with egfr mutations |
| US12037346B2 (en) | 2021-04-13 | 2024-07-16 | Nuvalent, Inc. | Amino-substituted heteroaryls for treating cancers with EGFR mutations |
| US11931420B2 (en) | 2021-04-30 | 2024-03-19 | Celgene Corporation | Combination therapies using an anti-BCMA antibody drug conjugate (ADC) in combination with a gamma secretase inhibitor (GSI) |
| WO2022235866A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Covalent ras inhibitors and uses thereof |
| WO2022235870A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors for the treatment of cancer |
| WO2022235864A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2022250170A1 (en) | 2021-05-28 | 2022-12-01 | Taiho Pharmaceutical Co., Ltd. | Small molecule inhibitors of kras mutated proteins |
| WO2023060253A1 (en) | 2021-10-08 | 2023-04-13 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2023056589A1 (en) | 2021-10-08 | 2023-04-13 | Servier Pharmaceuticals Llc | Menin inhibitors and methods of use for treating cancer |
| WO2023114954A1 (en) | 2021-12-17 | 2023-06-22 | Genzyme Corporation | Pyrazolopyrazine compounds as shp2 inhibitors |
| EP4227307A1 (en) | 2022-02-11 | 2023-08-16 | Genzyme Corporation | Pyrazolopyrazine compounds as shp2 inhibitors |
| WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
| WO2023211812A1 (en) | 2022-04-25 | 2023-11-02 | Nested Therapeutics, Inc. | Heterocyclic derivatives as mitogen-activated protein kinase (mek) inhibitors |
| WO2023240263A1 (en) | 2022-06-10 | 2023-12-14 | Revolution Medicines, Inc. | Macrocyclic ras inhibitors |
| WO2024006542A1 (en) | 2022-06-30 | 2024-01-04 | Sutro Biopharma, Inc. | Anti-ror1 antibodies and antibody conjugates, compositions comprising anti-ror1 antibodies or antibody conjugates, and methods of making and using anti-ror1 antibodies and antibody conjugates |
| WO2024010925A2 (en) | 2022-07-08 | 2024-01-11 | Nested Therapeutics, Inc. | Mitogen-activated protein kinase (mek) inhibitors |
| WO2024081916A1 (en) | 2022-10-14 | 2024-04-18 | Black Diamond Therapeutics, Inc. | Methods of treating cancers using isoquinoline or 6-aza-quinoline derivatives |
| WO2024206858A1 (en) | 2023-03-30 | 2024-10-03 | Revolution Medicines, Inc. | Compositions for inducing ras gtp hydrolysis and uses thereof |
| WO2024211663A1 (en) | 2023-04-07 | 2024-10-10 | Revolution Medicines, Inc. | Condensed macrocyclic compounds as ras inhibitors |
| WO2024211712A1 (en) | 2023-04-07 | 2024-10-10 | Revolution Medicines, Inc. | Condensed macrocyclic compounds as ras inhibitors |
| WO2024216016A1 (en) | 2023-04-14 | 2024-10-17 | Revolution Medicines, Inc. | Crystalline forms of a ras inhibitor |
| WO2024216048A1 (en) | 2023-04-14 | 2024-10-17 | Revolution Medicines, Inc. | Crystalline forms of ras inhibitors, compositions containing the same, and methods of use thereof |
| WO2024226579A1 (en) | 2023-04-24 | 2024-10-31 | Nested Therapeutics, Inc. | Heterocyclic derivative as mitogen-activated protein kinase (mek) inhibitor |
| WO2024229406A1 (en) | 2023-05-04 | 2024-11-07 | Revolution Medicines, Inc. | Combination therapy for a ras related disease or disorder |
| US12440491B2 (en) | 2023-06-23 | 2025-10-14 | Amgen Inc. | KRAS G12C inhibitors and methods of using the same |
| WO2025034702A1 (en) | 2023-08-07 | 2025-02-13 | Revolution Medicines, Inc. | Rmc-6291 for use in the treatment of ras protein-related disease or disorder |
| WO2025043187A1 (en) | 2023-08-24 | 2025-02-27 | Otsuka Pharmaceutical Co., Ltd. | Fixed dose combinations of cedazuridine and azacitidine |
| WO2025080946A2 (en) | 2023-10-12 | 2025-04-17 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2025081117A2 (en) | 2023-10-13 | 2025-04-17 | Sutro Biopharma, Inc. | Anti-tissue factor antibodies and antibody conjugates, compositions comprising anti-tissue factor antibodies or antibody conjugates, and methods of making and using anti-tissue factor antibodies and antibody conjugates |
| WO2025085748A1 (en) | 2023-10-20 | 2025-04-24 | Merck Sharp & Dohme Llc | Small molecule inhibitors of kras proteins |
| WO2025090905A1 (en) | 2023-10-26 | 2025-05-01 | Nested Therapeutics, Inc. | Crystalline forms of 3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-7-[(3-fluoro-2-pyridyl)oxy]-4-methyl-chromen-2-one |
| WO2025137507A1 (en) | 2023-12-22 | 2025-06-26 | Regor Pharmaceuticals, Inc. | Sos1 inhibitors and uses thereof |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0813520B1 (en) | Arylsulfonylamino hydroxamic acid derivatives | |
| KR100219976B1 (en) | Derivatives of arylsulfonyl hydroxamic acid | |
| US6153609A (en) | Arylsulfonylamino hydroxamic acid derivatives | |
| EP0895988B1 (en) | Arylsulfonylamino hydroxamic acid derivatives | |
| AU721748B2 (en) | Arylsulfonylamino hydroxamic acid derivatives | |
| EP0966438A1 (en) | N-hydroxy-beta-sulfonyl-propionamide derivatives and their use as inhibitors of matrix metalloproteinases | |
| EP0818442A2 (en) | Cyclic sulphone derivatives as inhibitors of metalloproteinases and of the production of tumour necrosis factor | |
| US5994351A (en) | Arylsulfonylamino hydroxamic acid derivatives | |
| US6107337A (en) | Arylsulfonylamino hydroxamic acid derivatives | |
| US6509337B1 (en) | Arylsulfonyl Hydroxamic Acid derivatives as MMP and TNF inhibitors | |
| US5883131A (en) | Cyclic sulfone derivatives | |
| KR100194258B1 (en) | Arylsulfonyl Hydroxamic Acid Derivatives | |
| MXPA99001808A (en) | Arylsulfonylamino hydroxamic acid derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WWE | Wipo information: entry into national phase | Ref document number:96193213.9 Country of ref document:CN | |
| AK | Designated states | Kind code of ref document:A1 Designated state(s):AL AM AT AU AZ BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IS JP KE KG KP KR KZ LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG US UZ VN AM AZ BY KG KZ MD RU TJ TM | |
| AL | Designated countries for regional patents | Kind code of ref document:A1 Designated state(s):KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN | |
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| WWE | Wipo information: entry into national phase | Ref document number:08894873 Country of ref document:US | |
| WWE | Wipo information: entry into national phase | Ref document number:PV1997-2782 Country of ref document:CZ | |
| ENP | Entry into the national phase | Ref document number:2214720 Country of ref document:CA Ref document number:2214720 Country of ref document:CA Kind code of ref document:A Ref document number:1996 526918 Country of ref document:JP Kind code of ref document:A | |
| WWE | Wipo information: entry into national phase | Ref document number:973613 Country of ref document:FI Ref document number:303860 Country of ref document:NZ Ref document number:1996907134 Country of ref document:EP | |
| WWE | Wipo information: entry into national phase | Ref document number:1019970706227 Country of ref document:KR | |
| WWE | Wipo information: entry into national phase | Ref document number:97/00913 Country of ref document:TR | |
| WWP | Wipo information: published in national office | Ref document number:1996907134 Country of ref document:EP | |
| REG | Reference to national code | Ref country code:DE Ref legal event code:8642 | |
| WWP | Wipo information: published in national office | Ref document number:1019970706227 Country of ref document:KR | |
| WWP | Wipo information: published in national office | Ref document number:PV1997-2782 Country of ref document:CZ | |
| WWR | Wipo information: refused in national office | Ref document number:1019970706227 Country of ref document:KR | |
| ENP | Entry into the national phase | Ref document number:2000 2000704128 Country of ref document:KR Kind code of ref document:A | |
| WWG | Wipo information: grant in national office | Ref document number:1996907134 Country of ref document:EP | |
| WWG | Wipo information: grant in national office | Ref document number:PV1997-2782 Country of ref document:CZ |